Relapsing Encephalopathy Research Articles

Genetically altered animal models for ATP1A3-related disorders.

ABSTRACTWithin the past 20 years, particularly with the advent of exome sequencing technologies, autosomal dominant and de novo mutations in the gene encoding the neurone-specific α3 subunit of the Na+,K+-ATPase (NKA α3) pump, ATP1A3, have been identified as the cause of a phenotypic continuum of rare neurological disorders. These allelic disorders of ATP1A3 include (in approximate order of severity/disability and onset in childhood development): polymicrogyria; alternating hemiplegia of childhood; cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome; relapsing encephalopathy with cerebellar ataxia; and rapid-onset dystonia-parkinsonism. Some patients present intermediate, atypical or combined phenotypes. As these disorders are currently difficult to treat, there is an unmet need for more effective therapies. The molecular mechanisms through which mutations in ATP1A3 result in a broad range of neurological symptoms are poorly understood. However, in vivo comparative studies using genetically altered model organisms can provide insight into the biological consequences of the disease-causing mutations in NKA α3. Herein, we review the existing mouse, zebrafish, Drosophila and Caenorhabditis elegans models used to study ATP1A3-related disorders, and discuss their potential contribution towards the understanding of disease mechanisms and development of novel therapeutics.

P.006 Role of repeat antithyroid antibody testing in the diagnosis of Hashimoto’s Encephalopathy

Background: We present a case of a previously well 71-year-old woman who developed rapidly progressive dementia. She had several prolonged hospital admissions and extensive investigations were performed. Her illness was steroid-responsive with clinical features suggestive of Hashimoto’s Encephalopathy (HE). However, multiple thyroid antibody panels acquired were initially normal, becoming elevated during subsequent relapses that occurred 3 years after initial presentation. The case signifies the importance of repeating antithyroid antibody levels in a patient with a clinical picture suggestive of HE. Methods: Case report. Results: The diagnosis of HE was established because of a compatible clinical picture including a relapsing encephalopathy with motor involvement and steroid responsiveness. In addition, although initial antithyroid antibody testing was negative, subsequent attacks were associated with significant elevations and reverted to normal with resolution of the attacks. Conclusions: In a patient with normal levels of antithyroid antibodies and a clinical presentation suggestive of HE, we recommend repeat antithyroid antibody testing to confirm diagnosis. Further studies are necessary to clarify the pathogenic role of elevated antithyroid antibodies in the mechanism of HE.

Communicating Hydrocephalus Associated with Relapsing Anti-N-Methyl-DAspartate Receptor (NMDAR) Encephalitis in an Adolescent Girl

Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is uncommon cause of immune mediated encephalopathy in children. It usually manifests as psychosis, seizures and dyskinesia. We describe an unusual association with the phenotype of this disease. An 11 year-old girl presented with psycho-behavioral disturbances, headache, fever and episodic disorientation few weeks after fever and upper respiratory tract infection. Her MRI showed communicating hydrocephalus. She was found to have positive anti-NMDAR antibodies. She underwent VP shunt followed by immunomodulatory therapy resulting in resolution of headache and substantial improvement of alertness and psycho-behavior. Several months later she relapsed and remission was induced by a repeated course of immunomodulatory therapy. This report illustrates the remarkable phenotypic variability in this condition. The diagnosis of anti-NMDAR encephalitis should be considered in patients who present with subacute or relapsing encephalopathy associated with communicating hydrocephalus.

The value of diffusion-weighted imaging in children with acute central nervous system symptoms

The value of diffusion-weighted imaging (DWI) in children with acute central nervous system (CNS) symptoms has not been fully established. We aimed to elucidate whether DWI gives additional information in children with acute CNS disorder. The subjects were eight children with acute CNS symptoms, whose cranial DWI showed signal abnormality. Two patients were suffered from cerebral infarction, and one had systemic lupus erythematosus with CNS involvement, four had acute encephalopathy, and one had relapsing encephalopathy. We retrospectively compared (1) the size of signal abnormality, (2) latency until appearance of signal abnormality, and (3) ability to differentiate old lesions between DWI and fluid-attenuation inversion recovery (FLAIR). In addition, we analyzed cerebral blood flow (CBF) changes in lesions detected by DWI, using single-photon emission computed topography (SPECT). In seven of eight patients, the size of signal abnormality was larger in DWI compared to FLAIR. In four of five patients with magnetic resonance imaging obtained during the very acute phase of CNS symptoms, the latency until appearance of signal abnormality was shorter on DWI compared to FLAIR. Combination of DWI and FLAIR successfully differentiated new lesions from old ones in all three subjects with a history of old lesions. DWI revealed signal abnormality not during the very acute phase but on 5th day of CNS symptoms in a patient with encephalopathy. In seven patients with SPECT available, lesions detected by DWI showed decreased CBF in four patients, increased CBF in two, normal CBF in one. DWI may provide useful additional information in children with acute CNS symptoms. Signal abnormalities on DWI may represent ischemic lesions or inflammatory lesions with increased or normal CBF on SPECT.

P59 – 2522: Steroid responsive photo-paroxysmal response in Hashimoto's encephalopathy

Objective To describe an unusual clinical and EEG phenotype of Hashimoto's encephalopathy. Methods A case report and discussion. Results Hashimoto's encephalopathy is rare progressive or relapsing encephalopathy syndrome associated with cognitive decline, seizures and myoclonus. We describe a six year old previously well girl who presented with gradual cognitive decline over a number of months. Work up for this revealed significantly raised thyroid peroxidase antibodies consistent with autoimmune thyroiditis. Therefore a diagnosis of Hashimoto's encephalopathy was made. She had no clinical seizures at presentation or follow up which is unusual for the described phenotype of paediatric Hashimoto's encephalopathy. Her MRI scans revealed global atrophy with multi-focal T2 white matter hyperintensities with no diffusion restriction. An EEG showed spike and polyspike wave complexes with background slowing and photo-paroxysmal responses at multiple frequencies. Other investigations including CSF, VLCFA's, ceruloplasmin, white cell enzymes and urine for organic acids were normal. She was commenced on steroids for Hashimoto's. She showed improvement and of note her previous EEG abnormalities had normalised as well as having no abnormal responses to photic stimulation. Conclusion The absence of prominent seizures is an unusual phenotype of Hashimoto's and presence of photo-paroxysmal responses has been described only in a few other cases in the literature. Our case illustrates that children presenting with Hashimoto's with evidence of CNS involvement should have an EEG including photic stimulation as this represents a potentially treatable entity within Hashimoto's even in those with no overt clinical seizures

Hashimoto’s Encephalopathy Presenting as Acute Psychosis

Background: Hashimoto’s encephalopathy is a relapsing encephalopathy occurring in association with Hashimoto’s thyroiditis, with high titers of anti-thyroid antibodies. Clinically the patients may presents with acute or subacute encephalopathy, seizure, myoclonus, and tremulousness, stroke like episode, amnesia or dementia. Here we are reporting a case of hashimoto’s encephalopathy who presented with features of acute psychosis. Case Report: A 56 years old Asian female presented with acute onset of altered behavioural abnormality and declining brain function. Serology revealed high anti thyroperoxidase antibodies. EEG and MRI were consistent with hashimoto’s encephalopathy. Conclusion: Hashimoto’s encephalopathy is a rare complication of hashimoto’s thyroiditis and is a diagnosis of exclusion and should be suspected in a case of encephalopathy, high anti thyroid antibodies and response to glucocorticoid.

N‐methyl‐D‐aspartate receptor antibodies in post–herpes simplex virus encephalitis neurological relapse

Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.

Surgical treatment for portosystemic encephalopathy in patients with liver cirrhosis: Occlusion of portosystemic shunt in combination with splenectomy

Operative ligation of the portosystemic shunt may control hepatic encephalopathy effectively, but the subsequent increase in portal vein pressure (PVP) leads to high mortality. Splenectomy can decrease inflow into the portal system, resulting in decreased portal pressure. We retrospectively examined the effect of splenectomy in combination with shunt closure on portosystemic encephalopathy. Clinical symptoms of encephalopathy disappeared in all six patients who underwent splenectomy in combination with portosystemic shunt ligation, with the exception of one patient who had relapsing encephalopathy after 6 months. Follow-up computed tomography showed complete obliteration of the portosystemic shunts, except in the one patient with relapsing encephalopathy who underwent balloon-occluded retrograde transvenous obliteration for the remaining splenorenal shunt 8 months after surgery. PVP significantly decreased after splenectomy. PVP did not increase to the baseline PVP value after ligation of the shunts, except in two patients who had elevated PVP after surgery: PVP increased from 18 to 19 mmHg after ligation in one patient and from 18 to 23 mmHg in one patient. Splenectomy followed by surgical ligation of the portosystemic shunt may be feasible and safe for cirrhotic patients with portosystemic shunts.

Hashimoto’s Encephalopathy in Children and Adolescents

Hashimoto's encephalopathy is an underdiagnosed, steroid-responsive, progressive or relapsing encephalopathy associated with high titers of serum antithyroid antibodies. Although Hashimoto's encephalopathy is well documented in adults, it is rarely observed or studied in children and adolescents. We describe the clinical and laboratory findings of four children (aged 9-15 years) with Hashimoto's encephalopathy. The clinical features of two patients at presentation included epileptic seizures and confusion. The other presenting signs included breath-holding spells, behavioral problems, psychosis, and ataxia (one patient each). During their presentation, three patients were euthyroid, and one was hyperthyroid. All patients manifested increased antithyroid antibodies, and all improved with steroid treatment. Hashimoto's encephalopathy is rarely suspected at presentation. Therefore, greater awareness of its signs by clinicians is necessary for proper diagnoses.

An adult onset case of alpha‐methyl‐acyl‐CoA racemase deficiency

α-Methyl-acyl-CoA-racemase (AMACR) deficiency (OMIM 604489) is a rare peroxisomal disorder with a variable age of onset from infancy to late adulthood. We describe a 45-year-old male with a history of seizures who presented with relapsing encephalopathy. Laboratory studies revealed an elevated serum pristanic acid concentration, an elevated pristanic/phytanic acid ratio, as well as the previously described homozygous mutation in the AMACR gene, c.154T>C, consistent with AMACR deficiency. This homozygous mutation is associated with a variable phenotype ranging from neonatal cholestasis to late-onset sensorimotor neuropathy. Dietary pristanic acid restriction was attempted to improve clinical status and the patient has remained in remission for more than 16 months.

Relapsing encephalopathy in a patient with α-methylacyl-CoA racemase deficiency

α-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features...

Relapsing encephalopathy following small bowel transplantation

We report a case of a 40-year-old man presenting with relapsing encephalopathy 4 years post-intestinal transplantation. Each episode was preceded by symptoms suggestive of subacute intestinal obstruction, marked dehydration, and, on one occasion, grade 4 encephalopathy. Physical examination revealed hypertonia, clonus, and hyperreflexia. Biochemistry was consistent with renal impairment, metabolic alkalosis, hyperammonaemia, and normal liver function. Plain radiographs and abdominal computed tomography revealed dilated proximal small bowel loops, and barium radiography demonstrated a strictured distal anastomosis. Hydrogen breath testing indicated bacterial overgrowth. Following rehydration and antibiotic therapy, the patient recovered fully between episodes. Further episodes of encephalopathy did not recur following resection of the distal anastomotic stricture and resolution of bacterial overgrowth. Unfortunately, one year later the patient died of pneumonia. To the best of our knowledge, encephalopathy secondary to intestinal transplant related porto-caval shunt and bacterial overgrowth in strictured bowel has not been previously reported but might have implications for the management of future patients.

Hashimoto's thyroiditis – a rare but treatable cause of encephalopathy in children

Hashimoto's encephalopathy is a very rare complication of Hashimoto's thyroiditis. It is a progressive or relapsing encephalopathy associated with elevation of thyroid specific autoantibodies. Patients usually present when euthyroid and this diagnosis should be considered in any unexplained encephalopathy or progressive cognitive decline in the euthyroid patient.

Hashirnoto's encephalopathy

We describe 5 patients with a relapsing encephalopathy in association with Hashimoto's disease and high titers of anti-thyroid antibodies. The presentation is usually with a subacute onset of confusion, alteration in conscious level, and focal or generalized seizures. The relapsing course, association with myoclonus or tremulousness, and episodes of stroke-like deterioration are characteristic features. The long-term prognosis is favorable with steroid therapy, though additional immunosuppressive therapy may be required. Neurologic investigation typically shows a diffusely abnormal EEG, high CSF protein level without pleocytosis, and normal brain CT and cerebral angiogram. Isotope brain scan may show patchy abnormal uptake. Hashimoto's encephalopathy should be recognized as a definite neurologic entity and added to the list of CNS complications of thyroid disease.

Acute relapsing encephalopathy with brain stem swelling, and necrotizing myopathy in a child

Acute relapsing encephalopathy with brain stem swelling, and necrotizing myopathy in a child