Case report: Acute vestibular syndrome and cerebellitis in anti-Yo paraneoplastic syndrome.

Background: We define acute vestibular syndrome (AVS) as a sudden onset vertigo, nausea, vomiting, and head motion intolerance, more frequently associated with an acute peripheral and unilateral vestibulopathy. About 10-20% of all cases with central vestibulopathy are secondary to stroke. We report three patients evaluated over the past decade with an acute AVS along with subtle downbeat nystagmus (DBN), followed by dysarthria and progressive truncal and limb ataxia, as well as increasing DBN intensity. Methods: All patients underwent neurologic examination, video-oculography, MRI, serum cancer markers, spinal fluid examination, paraneoplastic panel testing, and oncologic workup. With a consolidated diagnosis of cancer/paraneoplastic syndrome, we treated with plasma exchange (PLEX), high-dose steroids, surgery, and oncologic investigation. We additionally provided oncotherapy in one out of three patients. Results: All three patients had an acute AVS, downbeat nystagmus DBN, and inability to perform tandem gait. Two of three patients had a normal head impulse test (HIT). As acute vertigo, nausea, and vomiting subsided, a progressive cerebellar syndrome ensued characterized by persistent DBN, impaired horizontal and vertical pursuit, impaired VOR suppression, truncal and limb ataxia, and dysarthria. All patients had normal MRI brain studies excluding stroke. CSF studies demonstrated lymphocytic pleocytosis and elevated protein. One patient had confirmed ovarian cancer with high CA-125 serum levels; another had undifferentiated cancer of unknown primary with high CA-125 and one patient with esophageal cancer. All had a positive PCA-1 antibody titer, also known as anti-Yo antibody. In one patient with expeditious immunosuppression, the ataxia progression slowed for 18 months, whereas the other two patients with delayed initiation of treatment had more rapidly progressive ataxia. Discussion: Paraneoplastic encephalitis related to PCA-1 antibody (Anti-Yo) targets Purkinje cells and cells in the granular layer of the cerebellar cortex. Clinically, our patients had a central AVS characterized by DBN and followed with progressive ataxia and unremarkable neuroimaging studies. Rapid initiation of treatment may offer a greater chance to prevent further neurologic decline. Any patient with an AVS as well as DBN and normal MRI should have an expeditious workup to rule out metabolic, toxic, and infectious causes just prior to considering prompt treatment with high-dose steroids and plasma exchange (PLEX) to mitigate the risk of rapidly progressive and irreversible neurologic decline.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Polysomnography Findings and Sleep Disorders in Children With Alternating Hemiplegia of Childhood.

STUDY OBJECTIVES: Patients with alternating hemiplegia of childhood (AHC) experience bouts of hemiplegia and other paroxysmal spells that resolve during sleep. Patients often have multiple comorbidities that could negatively affect sleep, yet sleep quality and sleep pathology in AHC are not well characterized. This study aimed to report sleep data from both polysomnography (PSG) and clinical evaluations in children with AHC. METHODS: We analyzed nocturnal PSG and clinical sleep evaluation results of a cohort of 22 consecutive pediatric patients with AHC who were seen in our AHC multidisciplinary clinic and who underwent evaluations according to our comprehensive AHC clinical pathway. This pathway includes, regardless of presenting symptoms, baseline PSG and evaluation by a board-certified pediatric sleep specialist. RESULTS: Out of 22 patients, 20 had at least one type of sleep problem. Six had obstructive sleep apnea as documented on polysomnogram, of whom two had no prior report of sleep-disordered breathing symptoms. Patients had abnormal mean overall apnea-hypopnea index of 5.8 (range 0-38.7) events/h and an abnormal mean arousal index of 15.0 (range 4.8-46.6) events/h. Based on sleep history, 16 patients had difficulty falling asleep, staying asleep, or both; 9 had behavioral insomnia of childhood; and 2 had delayed sleep-wake phase syndrome. CONCLUSIONS: Sleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG.

Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction.

OBJECTIVE: Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable. METHODS: We performed extracellular recordings, as well as whole-cell patch clamp recordings from pyramidal cells and interneurons, in the CA1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA1 pyramidal cells as well as parvalbumin-positive interneurons. In addition, we performed video-electroencephalography (EEG) recordings from the dorsal hippocampal CA1 region. RESULTS: We observed that juvenile knock-in mice carrying the above mutation reproduce the human phenotype of AHC. We then demonstrated in the CA1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in CA1 fast-spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons. SIGNIFICANCE: Our data indicate that, in our genetic model of Atp1α3 mutation, there is increased excitability and marked dysfunction in GABAergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABAergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.