Progressive Neurological Syndrome Research Articles

Fanconi anemia neuroinflammatory syndrome: brain lesions and neurologic injury in Fanconi anemia

AbstractFanconi anemia (FA) is a complex inherited bone marrow failure syndrome characterized by chromosomal instability and defective DNA repair, causing sensitivity to DNA interstrand crosslinking agents. Our understanding of the full adult phenotype of the disease continues to evolve, because most patients with FA died of marrow failure in the first decade of life before more recent advances in allogeneic hematopoietic cell transplantation. Herein, we report a previously undescribed, clinically concerning, progressive neurologic syndrome in patients with FA. Nine nonimmunosuppressed pediatric patients and young adults with FA presented with acute and chronic neurological signs and symptoms associated with distinct neuroradiological findings. Symptoms included, but were not limited to, limb weakness, papilledema, gait abnormalities, headaches, dysphagia, visual changes, and seizures. Brain imaging demonstrated a characteristic radiographic appearance of numerous cerebral and cerebellar lesions with associated calcifications and often a dominant ring-enhancing lesion. Tissue from the dominant brain lesions in 4 patients showed nonspecific atypical glial proliferation, and a small number of polyomavirus-infected microglial cells were identified by immunohistochemistry in 2 patients. Numerous interventions were pursued across this cohort, in general with no improvement. Overall, these patients demonstrated significant progressive neurologic decline. This cohort highlights the importance of recognizing FA neuroinflammatory syndrome, which is distinct from malignancy, and warrants careful ongoing evaluation by clinicians.

Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants.

Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities and renal impairment. So far it has been reported in only two families. We describe the clinical phenotype of eight further individuals from four unrelated families with SLC30A9-related disease. Following detailed clinical phenotyping, one family underwent research whole-genome sequencing (WGS), one research whole-exome sequencing (WES) and two diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modelling and where relevant, sequencing of cDNA for splicing impact. In two unrelated families of Pakistani origin (one consanguineous, one not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included two affected brothers, and Family 2 one affected boy. In Family 3, also consanguineous, there were four affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was non-consanguineous: the one affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5 and c.1413A>G, p.Ser471=. Despite phenotypic variability between the four families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modelling. Its presence in two unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an impact on splicing was confirmed through cDNA analysis. Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurological syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognised.

Clinical Screening for Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a progressive neurologic syndrome that presents with complex visual deficits. Although PCA is most commonly a form of Alzheimer disease (AD), its early diagnosis is usually delayed due to a lack of understanding for how best to clinically screen for the syndrome. To identify neurobehavioral screening tasks for PCA-beyond simple visual constructions-that can be administered in clinic or at bedside. We compared the performance of 12 individuals who met neuroimaging-supported consensus criteria for PCA with that of 12 matched individuals with typical AD (tAD) and 24 healthy controls (HC) on clinic/bedside tasks measuring (a) complex figure copying, (b) Balint syndrome, (c) visual object agnosia, (d) color identification, (e) figure-ground discrimination, (f) global-local processing, (g) dressing apraxia, (h) ideomotor apraxia, and (i) Gerstmann syndrome. All of the individuals with PCA were impaired on the figure-ground discrimination task compared with half of the tAD group and no HC. Approximately half of the PCA group had Balint syndrome, dressing apraxia, and ideomotor apraxia compared with none in the tAD group. Difficulty copying a complex figure, global-local processing impairment, and Gerstmann syndrome did not distinguish between the two dementia groups. The figure-ground discrimination task can be used successfully as an overall screening measure for PCA, followed by specific tasks for Balint syndrome and dressing and limb apraxia. Findings reinforce PCA as a predominant occipitoparietal disorder with dorsal visual stream involvement and parietal signs with spatiomotor impairments.

Morphological and morphometric changes in the Purkinje cells of patients with essential tremor.

Essential tremor (ET) is a progressive neurological syndrome characterised by involuntary tremors of the hands or arms, head, jaw and voice. The pathophysiology of ET is not clearly understood yet. However, previous studies have reported several changes in the brain of patients with ET. One of the brain areas extensively investigated is the cerebellum. In the present study, a morphometric analysis of Purkinje cells in patients with ET and ET-plus was performed, and subsequently compared with normal controls using the Golgi silver staining method and 3D neuronal reconstruction. Substantial morphological changes were uncovered in the Purkinje cells of patients with ET compared with normal controls, including a decreased dendritic length and field density, an overall loss of terminal branches and a decreased density of dendritic spines.

Paraneoplastic neurological syndrome associated with anti-amphiphysin antibodies misleaded the diagnosis of Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) and neurological paraneoplastic disease may present similar clinical features. Establishing the correct diagnosis has practical relevance in the care management for these patients. The objective of the present study is to determine how the diagnosis of Creutzfeldt-Jakob disease may be differentiated from several rapidly progressive neurological syndromes.

A Case of Recurrent Acute Abdomen in a Young Lady Masquerading as Somatoform Disorder

Acute intermittent porphyria (AIP) is a rare autosomal dominant hereditary metabolic disorder having protean manifestations. It usually presents with short duration of gastrointestinal symptoms followed by rapidly progressive fulminant neurological syndrome. It is a neurological emergency and mimics many other psychiatric and medical disorders and can be fatal if it remains undiagnosed and untreated. Further, specific treatment in the form of Heme arginate is not universally available and very costly, so high clinical suspicion and early diagnosis and management of acute attack and prevention of further attacks are very important. Here, we report a 23 years old married female nurse presenting with recurrent acute abdomen requiring frequent hospital admissions along with convulsion during her last attack. The presence of porphyrins in urine confirms the diagnosis of AIP.

Neuropsychological and neuroimaging characteristics of classical superficial siderosis.

To define the neuropsychological and neuroimaging characteristics of classicalinfratentorial superficial siderosis (iSS), a rare but disabling disorder defined by hemosiderin deposition affecting the superficial layers of the cerebellum, brainstem and spinal cord, usually associated with a slowly progressive neurological syndrome of deafness, ataxia and myelopathy. We present the detailed neuropsychological and neuroimaging findings in 16 patients with iSS (mean age 57years; 6 female). Cognitive impairment was present in 8/16 (50%) of patients: executive dysfunction was the most prevalent (44%), followed by impairment of visual recognition memory (27%); other cognitive domains were largely spared. Disease symptom duration was significantly correlated with the number of cognitive domains impaired (r = 0.59, p = 0.011). Mood disorders were also common (anxiety 62%, depression 38%, both 69%) but not associated with disease symptom duration. MRI findings revealed siderosis was not only in infratentorial brain regions, but also in characteristic widespread symmetrical supratentorial brain regions, independent of disease duration and degree of cognitive impairment. The presence of small vessel disease markers was very low and did not account for the cognitive impairment observed. Neuropsychological disturbances are common in iSS and need to be routinely investigated. The lack of association between the anatomical extent of hemosiderin and cognitive impairment or disease duration suggests that hemosiderin itself is not directly neurotoxic. Additional biomarkers of iSS disease severity and progression are needed for future research and clinical trials.

In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6–12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.

Staged surgical treatment of brachioplexopathy in an adolescent with Klippel-Feil syndrome: a rare clinical case and literature review

Klippel-Feil syndrome is a congenital malformation, the leading component of which is a violation of segmentation of the cervical vertebral bodies. The syndrome can be combined with other skeletal anomalies: skull asymmetry, scoliosis, high shoulder blades, and cervical ribs. Treatment of the syndrome is usually symptomatic; indications for surgical treatment are progressive neurological disorders and persistent pain syndrome, which usually develop due to instability of unblocked segments, or neurogenic pain. A clinical case of treatment of a 17-year-old patient with Klippel-Feil syndrome who developed a picture of severe upper limb monoparesis during three years due to compression of the brachial plexus associated with cervical ribs is presented. Decompression of the brachial plexus was performed, which led to rapid relief of pain syndrome and gradual partial regression of motor disorders. Due to incomplete restoration of the gripping function, tendon-muscle plasty of the right hand was performed, which significantly improved the possibility of self-care. The results of radiation and staged neurophysiological studies are described, as well as a review of the literature on the Klippel-Feil syndrome.

A Commonly Missed Well Known Entity- Acute Intermittent Porphyria: A Case Report

Acute intermittent porphyria (AIP) is a rare autosomal dominant hereditary metabolic disorder having protean manifestations. It usually presents with short duration of gastrointestinal symptoms followed by rapidly progressive fulminant neurological syndrome. It is a neurological emergency and mimics many other psychiatric and medical disorders and can be fatal if it remains undiagnosed and untreated. Further, specific treatment in the form of Heme arginate is not universally available and very costly, so high clinical suspicion and early diagnosis and management of acute attack and prevention of further attacks are very important. Here, we report a 23 years old married female nurse presenting with recurrent acute abdomen requiring frequent hospital admissions along with convulsion during her last attack. The presence of porphyrins in urine confirms the diagnosis of AIP.

A Young Lady with Recurrent Acute Abdomen

Acute intermittent porphyria (AIP) is a rare autosomal dominant hereditary metabolic disorder having protean manifestations. It usually presents with short duration of gastrointestinal symptoms followed by rapidly progressive fulminant neurological syndrome. It is a neurological emergency and mimics many other psychiatric and medical disorders and can be fatal if it remains undiagnosed and untreated. Further, specific treatment in the form of Heme arginate is not universally available and very costly, so high clinical suspicion and early diagnosis and management of acute attack and prevention of further attacks are very important. Here, we report a 23 years old married female nurse presenting with recurrent acute abdomen requiring frequent hospital admissions along with convulsion during her last attack. The presence of porphyrins in urine confirms the diagnosis of AIP.

Long lasting trigeminal neuropathy, limbic encephalitis and abdominal ganglionitis without primary cancer: An atypical case of Hu-antibody syndrome

ObjectivesAnti-Hu antibodies (Hu-Abs) are the most frequent onconeural antibodies associated with paraneoplastic neurologic syndromes (PNS). PNS include a variety of neurological syndromes, affecting less than 1/10,000 patients with cancer. In the majority of cases, PNS will manifest before the malignancy is diagnosed. We found a case in which PNS was diagnosed without finding a primary malignancy after extensive work-up and even post-mortem autopsy. Patient and methodsWe present a case report of a 58-year-old man. This article includes extensive clinical work-up, full-body autopsy and brain autopsy with classical histochemical and myelin stainings and immunohistochemistry was performed. ResultsThe patient developed a progressive trigeminal neuropathy over a period of 5 years, in combination with cerebellar degeneration, asymmetrical brainstem and limbic encephalitis. Serum showed repeatedly high anti-Hu antibodies. Comprehensive cancer screening could not demonstrate any primary malignancy. Therapy with corticosteroids, plasma exchange, cyclophosphamide and rituximab showed no beneficial effect. He died from the complications of enteric ganglionitis 5 years after onset of the first symptoms. A postmortem autopsy could not detect a primary malignancy either. Brain morphology is described in detail. ConclusionParaneoplastic anti-Hu encephalitis cases associated with SCLC or other primary neoplasms are well known. An adult with a progressive multifocal neurological syndrome in the presence of positive anti-Hu antibodies, but without any primary neoplasm after a follow-up over 5 years is unusual.

MYORG Mutations: a Major Cause of Recessive Primary Familial Brain Calcification

Until recently, the gene associated with the recessive form of familial brain calcification (PFBC, Fahr disease) was unknown. MYORG, a gene that causes recessive PFBC was only recently discovered and is currently the only gene associated with a recessive form of this disease. Here, we review the radiological and clinical findings in adult MYORG mutation homozygous and heterozygous individuals. MYORG was shown to be the cause of a large fraction of recessive cases of PFBC in patients of different ethnic populations. Pathogenic mutations include inframe insertions and deletions in addition to nonsense and missense mutations that are distributed throughout the entire MYORG coding region. Homozygotes have extensive brain calcification in all known cases, whereas in some carriers of heterozygous mutation, punctuated calcification of the globus pallidus is demonstrated. The clinical spectrum in homozygotes ranges from the lack of neurological symptoms to severe progressive neurological syndrome with bulbar and cerebellar signs, parkinsonism and other movement disorders, and cognitive impairments. Heterozygotes are clinically asymptomatic. MYORG is a transmembrane protein localized to the endoplasmic reticulum and is mainly expressed in astrocytes. While the biochemical pathways of the protein are still unknown, information from its evolution profile across hundreds of species (phylogenetic profiling) suggests a role for MYORG in regulating ion homeostasis via its glycosidase domain. MYORG mutations are a major cause for recessive PFBC in different world populations. Future studies are required in order to reveal the cellular role of the MYORG protein.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection.

Background: Essential tremor (ET) is a common, progressive neurological syndrome with bilateral upper-limb dysfunction of at least 3-year duration, with or without tremor in other body locations. This disorder has a negative impact on daily function and quality of life. A single oral therapy has been approved by FDA for ET. Off-label pharmacotherapies have inadequate efficacy and poor tolerability with high rates of patient dissatisfaction and discontinuation. Safe and efficacious pharmacotherapies are urgently needed to decrease tremor and improve daily living. T-CALM (Tremor-CAv3 modulation) protocol is designed to assess safety and efficacy of CX-8998, a selective modulator of the T-type calcium channel, for ET therapy.Methods/Design: T-CALM is a phase 2, proof of concept, randomized, double-blind, placebo-controlled trial. Titrated doses of CX-8998 to 10 mg BID or placebo will be administered for 28 days to moderate to severe ET patients who are inadequately treated with existing therapies. The primary endpoint will be change from baseline to day 28 of The Essential Tremor Rating Assessment Performance Subscale (TETRAS-PS). Secondary efficacy endpoints for clinician and patient perception of daily function will include TETRAS Activity of Daily Living (ADL), Quality of Life in Essential Tremor Questionnaire (QUEST), Clinical Global Impression-Improvement (CGI-I), Patient Global Impression of Change (PGIC), and Goal Attainment Scale (GAS). Kinesia One, Kinesia 360, and iMotor will biometrically evaluate motor function and tremor amplitude. Safety will be assessed by adverse events, physical and neurological exams and laboratory tests. Sample size of 43 patients per group is estimated to have 90% power to detect a 5.5-point difference between CX-8998 and placebo for TETRAS-PS. Efficacy analyses will be performed with covariance (ANCOVA) and 2-sided test at 0.05 significance level.Discussion: T-CALM has a unique design with physician rating scales, patient-focused questionnaires and scales and objective motor measurements to assess clinically meaningful and congruent efficacy. Patient perception of ET debilitation and therapy with CX-8998 will be key findings. Overall goal of T-CALM is generation of safety and efficacy data to support a go, no-go decision to further develop CX-8998 for ET. Design of T-CALM may guide future clinical studies of ET pharmacotherapies.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03101241

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in theearly postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Supporting the carers of people with dementia

Dementia is a progressive neurological syndrome. Because of its complexity and longevity, dementia can have a negative effect on the health of informal carers, including spouses, family members and friends. Carers of people with dementia are at increased risk of depression and some long-term conditions; however, there are interventions that nurses can implement to support them. This article reviews the effect that caring has on carers of people with dementia, while exploring how nurses can provide optimal support through care planning, signposting to external services and understanding the importance of the role of carers.

Supporting the carers of people with dementia.

Dementia is a progressive neurological syndrome. Because of its complexity and longevity, dementia can have a negative effect on the health of informal carers, including spouses, family members and friends. Carers of people with dementia are at increased risk of depression and some long-term conditions; however, there are interventions that nurses can implement to support them. This article reviews the effect that caring has on carers of people with dementia, while exploring how nurses can provide optimal support through care planning, signposting to external services and understanding the importance of the role of carers.

Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort.

Cerebrospinal fluid (CSF) tau and neurofilament light chain (NF-L) proteins have proved to be reliable biomarkers for neuronal damage; however, there is a strong need for blood-based tests. The present study included 132 autopsy cases with rapidly progressive neurological syndromes, including Alzheimer disease (AD) (21), sporadic (65) and genetic (21) Creutzfeldt-Jakob disease (CJD), 25 cases with vascular, neoplastic and inflammatory alterations, and additionally 18 healthy control individuals. CSF tau and NF-L concentrations were measured by enzyme-linked immunosorbent assay. Plasma tau and NF-L concentrations were measured using ultra-sensitive single molecule array technology. Plasma and CSF tau (R = 0.59, P < 0.001) and NF-L (R = 0.69, P < 0.001) levels correlated significantly (Spearman test). Plasma tau and NF-L levels were significantly higher in all disease groups compared to healthy controls (P < 0.001). Receiver operating characteristic curves were used and area under the curve values for comparisons with controls were 0.82 (AD), 0.94 (sporadic CJD), 0.92 (genetic CJD) and 0.83 (other neurological disorders) for plasma tau and 0.99, 0.99, 1.00 and 0.96 for plasma NF-L, respectively. Molecular subtyping of sporadic CJD showed a strong effect (linear logistic regression) on plasma tau (P < 0.001) but not NF-L levels (P = 0.19). Plasma tau and NF-L concentrations are strongly increased in CJD and show similar diagnostic performance to the corresponding CSF measure. Molecular subtypes of sporadic CJD show different levels of plasma tau. Although not disease-specific, these findings support the use of plasma tau and NF-L as tools to identify, or to rule out, neurodegeneration.

Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase

BackgroundA decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety.MethodsSingle doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report.ResultsAn acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.ConclusionsAn unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.

Non-operative management: An evidence-based approach

Symptomatic lumbar disc herniation is a common problem encountered in both surgical and non-surgical practices. The decision between surgical and non-surgical management of this entity can be challenging for both the patient and the treating physician. A variety of non-surgical treatment options exist, many with poor evidence supporting their efficacy. Treatment algorithms are available to promote improved outcomes and cost-effectiveness and reduce unnecessary interventions. In the absence of progressive neurologic deficit or cauda equina syndrome, non-surgical treatments for symptomatic lumbar disc herniations are typically implemented for at least 6 weeks with good results. The following is an evidence-based review of the non-surgical management of symptomatic lumbar disc herniation.