Alternating hemiplegia of childhood: clinical manifestations and long-term outcome

We present our analysis of 44 patients with alternating hemiplegia of childhood. The clinical course usually consisted of three phases. The first was dominated by abnormal eye movements and dystonic episodes, the second by hemiplegic spells and psychomotor regression, and the third by persistent developmental delay and fixed neurologic deficits. The age of onset was 0-54 months (mean = 7.9 +/- 13 months). The presenting signs included abnormal ocular movements in 65%, dystonia in 60%, and hemiplegia in 32%. Patients with an early onset of the disorder and an early appearance of hemiplegic spells faired the poorest developmentally. Developmental delay was present in 91%, ataxia in 68%, choreoathetosis in 50%, and seizures in 18%. Laboratory investigations suggested mitochondrial abnormalities and cerebrovascular dysfunction in several patients. Numerous therapies were largely ineffective. Flunarizine reduced the duration, severity, and frequency of the hemiplegic attacks in 78%. Patients who received flunarizine did not differ developmentally from those who did not. Our data suggest that flunarizine does not adversely affect and may favorably influence the outcome in patients with alternating hemiplegia of childhood. Additionally, the occurrence of autosomal-dominant cases of the syndrome, although rare, suggests that, in addition to mitochondrial dysfunction, genetic factors may be important.     

Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using ³¹P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turNovemberer at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.     

Alternating hemiplegia of childhood in half-sisters

We present the family of two girls affected with alternating hemiplegia of childhood who were born to the same mother and different fathers. Previous reports suggested mitochondrial dysfunction as an etiologic mechanism for this disorder. Muscle biopsy, including a measurement of the respiratory chain enzymes, performed in one of the sisters showed no mitochondrial abnormalities. The mode of inheritance is not certain, but an autosomal-dominant gene is most likely.     

Alternating hemiplegia of childhood: a syndrome inherited with an autosomal dominant trait

Alternating hemiplegia of childhood is a rare disorder characterized by recurrent attacks of hemiplegia affecting either side of the body, oculomotor and autonomic disturbances, movement disorders, and progressive cognitive impairment. We report on one family with autosomal dominant alternating hemiplegia. The disorder was first recognized in a 9-year-old child, the third son of the family, who presented with learning disability, tonic-clonic seizures, dystonic attacks, and episodes of alternating hemiplegia starting at the age of 2 1/2 years. His mother and three brothers had similar symptoms. The maternal uncle, who has learning disability, had experienced multiple dystonic attacks. Tests performed on the family, including computerized tomography, magnetic resonance imaging, and magnetic resonance angiography of the brain as well as metabolic evaluation, were normal. Cytogenetic analysis was normal and mitochondrial DNA analysis revealed no deletions or mutations in the four affected family members and the grandmother. An autosomal dominant mode of inheritance is suggested by the fact that both sexes are affected in two generations.     

儿童交替性偏瘫的临床特征和脑血流灌注改变

目的探讨儿童交替性偏瘫的临床特点及脑血流改变。方法对近23年收治的11例患儿的临床资料进行分析,并对6例患儿应用单光子发射计算机断层扫描进行脑血流灌注观察,其中4例在发作间期,1例在发作期,1例在发作间期和发作期均进行测定,以兴趣区法作半定量分析。结果11例患儿的临床特征一般为18个月内起病,表现为频繁发作的交替性偏瘫、短暂的眼球震颤、肌张力异常、舞蹈徐动样动作,常伴自主神经功能紊乱和认知功能减退;睡眠可缓解上述症状。2次发作期单光子发射计算机断层扫描均示偏瘫对侧脑血流减少,5次发作间期均正常。结论本病的主要临床特征为一般18个月内起病的反复发作的交替性偏瘫,伴锥体外系症状及智能障碍;发作期偏瘫对侧脑血流减少。     

Alpha[11C] methyl-L-typtophan positron emission tomography in patients with alternating hemiplegia of childhood

Based on previous reports suggesting a role of the neurotransmitter serotonin in the pathomechanism of alternating hemiplegia of childhood and speculation that it may be a migraine variant, we measured brain serotonin synthesis in children with alternating hemiplegia of childhood. Clinical and neurodevelopmental data, as well as standard uptake values in 25 brain regions and whole-brain serotonin synthesis capacity (unidirectional uptake rate constant or K-complex), were assessed in six patients with alternating hemiplegia of childhood (three girls and three boys; mean age = 7 6/12 years) using alpha[11C]methyl-L-tryptophan positron emission tomography (PET). The PET studies were performed interictally in three patients, during the ictal state in two patients, and postictally in one patient. The PET data were compared to those obtained interictally from six age-matched patients with focal epilepsy (two girls and four boys; mean age = 7 8/12 years) and six non-age-matched apparently normal siblings of autistic children (two girls and four boys; mean age = 9 11/12 years). Patients with alternating hemiplegia of childhood studied in the ictal or postictal state showed increased serotonin synthesis capacity in the frontoparietal cortex, lateral and medial temporal structures, striatum, and thalamus when compared to controls, and subjects with alternating hemiplegia of childhood studied interictally. The involvement of these brain regions was consistent with the semiology of the hemiplegic attacks. In patients with interictal studies and in the controls, the PET scans revealed similar and bilaterally symmetric regional patterns of serotonin synthesis capacity. Increased whole-brain serotonin synthesis capacity (reported in migraine subjects without aura) was not found in the alternating hemiplegia of childhood group. There was no correlation between the neurodevelopmental scores and regional standard uptake values; however, patients with a larger estimated lifetime attack number showed greater delay in communication (P = .005) and daily living skills (P = .042). These studies suggest increased regional serotonergic activity associated with attacks in alternating hemiplegia of childhood. Furthermore, the attack number may have an effect on neurodevelopmental delay, thus supporting the notion that alternating hemiplegia of childhood may be a progressive disorder.     

不同年龄组儿童急性偏瘫伴随症状与病因的关系

目的 探讨儿童不同年龄组急性偏瘫伴随症状和病因的关系。方法 对2007-2009年本院收治的31例急性偏瘫患儿的临床资料进行回顾性分析。结果 31例患儿中，＜1岁5例，＞1～3岁12例，＞3～6岁儿童4例，＞6岁年长儿10例。主要伴随症状：惊厥21例、发热12例、意识障碍10例。急性偏瘫的主要病因：①脑血管病10例：其中脑血管畸形4例（幼儿3例、学龄儿1例）、外伤性脑梗死2例（学龄前）、合并先天性代谢缺陷病（同型半胱氨酸血症）2例；②中枢神经系统感染9例（<1岁4例）；③先天代谢性缺陷病5例（均为年长儿）；④偏侧惊厥偏瘫综合征/偏侧惊厥偏瘫癫痫综合征（hemiconvulsion-hemiplegia/hemiconvulsion-hemiplegia-epilepsy syndrome，HH/HHE）4例；交替性偏瘫2例；⑤其他：维生素K1缺乏性颅内出血、急性播散性脑脊髓炎和脑干肿瘤各1例。结论 ①小儿急性偏瘫病因繁多，各年龄段均有发病，其中1～3岁所占比例最大；②偏瘫主要伴随症状有惊厥、发热、意识障碍；伴随症状不同其病因各异；③婴幼儿主要病因是中枢神经系统感染，幼儿和学龄前期儿童中外伤性脑梗死和脑血管畸形并不少见；先天性代谢缺陷病是年长儿偏瘫的病因之一。     

Single photon emission computed tomography findings in a case of alternating hemiplegia of childhood in relation to migraine

Single photon emission computed tomography (SPECT) was performed 3 times during attacks and performed 4 times during postictal periods on a case of alternating hemiplegia of childhood. Hyperperfusion of the corresponding hemisphere to hemiparesis was suggested by asymmetric increase RI uptake during the ictal scans, whereas interictal scans showed symmetric topography of cerebral blood flow. Manifestations except hemiplegia included loss of consciousness and vomiting. These manifestations and ictal SPECT findings are the same evidence as hemiplegic migraine. It suggests that these two disorders have a similar pathophysiology. There are two interesting findings regarding this patient. The first finding is magnetic resonance imaging showed progressive cerebellar atrophy. Second finding is interictal SPECT showed a progressive decrease of cerebral perfusion, especially in cerebellar hemispheres. These two findings suggest alternating hemiplegia of childhood may be a chronic progressive disorder.     

儿童交替性偏瘫六例分析

目的探讨儿童交替性偏瘫（ＡＨＣ）的临床特点及治疗方法。方法对６例ＡＨＣ患儿的临床资料进行分析。结果６例患儿的临床特征为出生后１８个月起内病，频繁发作，持续数分钟至数小时；短暂的眼球震颤，肌张力异常，舞蹈徐动样动作，植物神经机能紊乱和认知机能减退；睡眠可缓解无力及锥体外系症状。应用氟桂嗪治疗后，１例患儿发作完全停止，其余５例患儿均显示发作频率和持续时间降低。结论本病的主要特征为１８个月内起病的发作性交替性偏瘫，伴锥体外系症状及智力障碍，氟桂嗪治疗本病有效     

Benign nocturnal alternating hemiplegia of childhood: six patients and long-term follow-up.

Benign familial nocturnal alternating hemiplegia of childhood refers to recurrent attacks of hemiplegia arising from sleep, described in young children without neurologic or mental impairment. It is probably migraine related. The authors report two unrelated patients with nocturnal attacks starting at 22 and 31 months, followed by daytime episodes in one. The authors confirm the benign course of this disorder. It is distinct from the classic malignant form of alternating hemiplegia of childhood.     

123I-iodoamphetamine SPECT brain imaging in alternating hemiplegia

Alternating hemiplegia of childhood is an unusual disorder characterized by early onset (occurring before 18 months of age); repeated attacks of hemiplegia involving both sides of the body; other paroxysmal phenomena, such as tonic stiffening, dystonic posturing, choreoathetoid movements, ocular motor abnormalities, and autonomic disturbances, in association with bouts of hemiplegia or occurring independently; and evidence of mental or neurologic deficits. A girl was examined because of left hemiplegia at the age of 16 months. The patient had begun exhibiting episodes of alternating hemiplegia at approximately 4 months of age. They consisted of tonic stiffening and dystonia of the right or left extremities, lasting from 30 min to several hours and followed by residual hemiparesis. They were invariably accompanied by ocular motor abnormalities. Magnetic resonance imaging, computed tomography, and angiography all were normal. Single proton emission computed tomography brain images during an acute episode of right hemiplegia demonstrated hypoperfusion of the left cerebral hemisphere. Following improvement of the hemiplegia, the patient was re-evaluated. The uptake of the radiotracer in the left hemisphere was increased. The scan did not demonstrate significant asymmetry in cerebral perfusion.     

An 11-year follow-up study of neonatal-onset, bath-induced alternating hemiplegia of childhood in twins

The authors previously reported on the initial manifestations in a set of female twins, who presented soon after birth with bath-induced paroxysmal events each time they were immersed in a warm water bath. These episodes progressively ceased by the age of 36 months, replaced by paroxysmal episodes of alternating hemiplegia unrelated to water immersion. By age 4 years, the twins developed the classic features of alternating hemiplegia of childhood. Clinical outcomes at the age of 11 years are now reported. Standard and video-electroencephalograms showed a large, slow background activity followed by lower amplitude waves without focal abnormalities or other abnormal findings. This represents the first report on (a) alternating hemiplegia of childhood started with bath-induced paroxysmal episodes; (b) this condition in monozygotic twins; and (c) an 11-year follow-up study in which the twins continue to experience episodes of alternating hemiplegia in the setting of baseline cognitive impairment without epileptic episodes.     

Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS

A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, in which a pituitary growth hormone (GH) secretion deficiency of hypothalamic origin was revealed through neuro-endocrinological examinations, was described. The case was a 10-year-old girl, who had been suffering from generalized tonic seizures since age 5, four episodes of alternating hemiplegia since age 6, stunted growth since age 7, and simple partial motor seizures as well as gelastic seizures since age 8. Marked elevation of lactate and pyruvate in both serum and CSF, abundant ragged red fibers in biopsied muscle, and low density areas in the left occipital lobe and bilateral globus pallidus in addition to diffuse brain atrophy on CT scan and MRI of the head were demonstrated, although the activities of muscle enzymes complex I-IV were within normal ranges. Pituitary GH secretion was deficient under the loadings with insulin, L-DOPA, sleep, and a single growth hormone releasing factor (GRF) administration, but normal GH response was registered under the repetitive stimulation with GRF. Activities of other hormonal axes were normal. It is likely that short stature commonly observed in MELAS patients is due to hypothalamic dysfunction, which might be brought out by chronic ischemia and energy deficiency of the diencephalon based upon mitochondrial abnormality of that region. It is likely that gelastic seizure in this case is due to hypothalamic dysfunction.     

Chemical pathology of acute demyelinating lesions and its correlation with disability

We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline-containing compounds, lactate, and myo-inositol inside the lesion acutely. Decreases in relative resonance intensities of N-acetylaspartate and creatine were seen both in and around the magnetic resonance imaging—detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo-inositol resonance intensities normalized during the follow-up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N-acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N-acetylaspartate resonance intensities and both brain lesion volumes (r = ?0.80, p < 0.0001) and clinical disability (r = ?0.73, p < 0.0001). As N-acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.     

Focal brain dysfunction in a 41-year old man with familial alternating hemiplegia

The acute pathophysiologic changes during hemiplegic spells and the long-term outcome of alternating hemiplegia remain obscure. In a 41-year-old male with familial alternating hemiplegia we found an increase in right frontal cerebral blood flow 3 h into a 5-h left hemiplegic episode. A repeat high-resolution brain SPECT study performed 26 h after the resolution of the left hemiplegia revealed normalization of the frontal blood flow accompanied by hyperperfusion in the right parietal lobe. An interictal SPECT scan several weeks later showed no asymmetries. Head CT and MRI scans were negative. Neuropsychologic assessment and neurologic examination revealed evidence of a diffuse disorder which predominantly involved the right hemisphere. To our knowledge, there are no previous correlative studies of serial highresolution brain SPECT with MRI, or of detailed neuropsychologic assessment, in adult patients with such an advanced course of alternating hemiplegia of childhood.     

Benign nocturnal alternating hemiplegia of childhood: Two cases with positive evolution

Benign nocturnal alternating hemiplegia (BNAH) of childhood is distinct from the classic form of malignant alternating hemiplegia of childhood [1]. It is characterized by hemiplegic attacks occurring exclusively during sleep [2]. It can be misdiagnosed as migraine, nocturnal frontal lobe epilepsy, benign rolandic epilepsy, Panayiotopoulos syndrome, or sleep-related movement disorder [1], [2], [3] and [4]. Only nine patients have been described to date, with typically, a normal development [1], [5], [6] and [7]. In order to insist about the benignity of the affection, we report two cases: a new three-year-old boy suffering from BNAH and a patient already published to show positive evolution at fourteen years of age. BNAH is a rare disorder but may be underdiagnosed. Making an early diagnosis can help to describe to the parents the good prognosis without treatment.     

In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease

We have investigated the sensitivity and specificity of a rapid phosphorus magnetic resonance spectroscopy (MRS) protocol for detecting metabolic abnormalities in vivo in skeletal muscle of patients with mitochondrial disease. We examined 17 patients with mitochondrial myopathies. Sixteen had only mild or minimal myopathic signs and symptoms. Phosphorus magnetic resonance spectra from the resting gastrocnemius muscles showed an abnormal intracellular energy state (marked by an increased intracellular inorganic phosphate concentration) in 14/17. In 3/17, this was associated with a decreased phosphocreatine concentration. We also studied 20 patients with other diseases of muscle (inflammatory myopathies, metabolic myopathies, muscular dystrophies, and myasthenia gravis) that can present with similar clinical features. Spectra showed increased intracellular inorganic phosphate concentrations in 6/20. All of these muscle diseases were associated with evidence of muscle fiber necrosis. Abnormalities in the muscle energy state in these cases may be due to secondary mitochondrial dysfunction. Except for cases of polymyositis and dermatomyositis, these 6 other myopathies could be readily distinguished from the mitochondrial myopathies on the basis of the clinical examination and blood tests. We conclude that phosphorus MRS of resting muscle is practical in a clinical setting and has a useful sensitivity and specificity for mitochondrial myopathies when used in conjunction with standard noninvasive tests.     

Topiramate: a new agent for patients with alternating hemiplegia of childhood

Alternating hemiplegia of childhood is a rare syndrome characterized by the onset, before 18 months of age, of frequent attacks of alternating paralysis. Here we report the efficacy of topiramate in four patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine, as well as in two newly diagnosed patients. Following treatment with topiramate, the frequency and duration of hemiplegic attacks significantly improved in all patients. Additional symptoms such as seizures, migraine, involuntary movements, autonomic symptoms, and impaired mental development also improved. Topiramate is worth trying when treating patients with AHC as a first trial, or a substitute for flunarizine once the latter agent loses effect.     

A patient with alternating hemiplegia in childhood

Alternating hemiplegia in childhood (Verret, 1971) is a disorder presenting with frequent episodes of alternating hemiplegia from early infancy. We report a patient with this disorder, along with a pathophysiological study and a discussion about the available therapies for this disorder. The patient, an 11-year-old boy, visited our hospital with episodes of alternating hemiplegia from early infancy. His family history showed that many members suffered from migraine. He was born with asphyxia. Mental and motor developmental delays were seen from early infancy. The hemiplegic episodes with ipsilateral facial palsy had occurred frequently from early infancy. The episodes were frequently induced by emotional stress. The duration of hemiplegia varied from 10 minutes to 3 days. From the age of 11 years, he had begun to have migrainous attacks with or without hemiplegic episodes. Neurological examination revealed slight muscle hypotonia, choreoathetosis and dystonic movements induced by locomotion, positive Myerson sign, increased deep tendon reflexes and Babinski reflex. CAG, VAG and CAT revealed normal findings. EEG revealed diffuse generalized slowing during hemiplegic episodes. Measurement of regional cerebral blood flow (CBF) by 133Xe inhalation method revealed a slight decrease of bilateral CBF during a quadriplegic episode. Positron emission tomography using C15O2 revealed a slight decrease of CBF at the insula, putamen and claustrum of the left side during a right sided episode. Increased excretion of urinary 5-HIAA was seen during one episode. From our clinical and laboratory findings, we think this disorder may be a special type of migraine. Therapeutic trials of diazepam and flunarizine were both effective, but the initial effectiveness was decreased after 5 months.