Neurological Disease Of Unknown Etiology Research Articles

Brain biopsy in neurological disease of unknown etiology: A single-center 12-year retrospective analysis.

There are no international guidelines for brain biopsy in neurological disease of unknown etiology, yet most practicing neurologists will encounter difficult cases in which biopsy is considered. This patient cohort is heterogenous, and it is unclear in which circumstances biopsy is most useful. We performed an audit of brain biopsies reviewed in our neuropathology department from 2010to2021. Of 9,488 biopsies, 331 biopsies undertaken for an undiagnosed neurological disease were identified. Where documented, the commonest symptoms were hemorrhage, encephalopathy, and dementia. 29% of biopsies were non-diagnostic. The most common clinically relevant findings on biopsy were infection, cerebral amyloid angiopathy with or without angiitis, and demyelination. Rarer conditions included CNS vasculitis, non-infectious encephalitis, and Creutzfeldt Jakob Disease. We highlight the value of brain biopsy in the workup of cryptogenic neurological disease despite recent advances in less invasive diagnostics.

Brain Biopsy for Neurological Diseases of Unknown Etiology in Critically Ill Patients: Feasibility, Safety, and Diagnostic Yield.

Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context. Monocenter, retrospective, observational cohort study. A French tertiary center. All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients. None. Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04). Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.

Letter to the Editor. Brain biopsy in children and adults with neurological diseases of unknown etiology: two sides of the same coin?

Letter to the Editor. Brain biopsy in children and adults with neurological diseases of unknown etiology: two sides of the same coin?

Neurological diseases of unknown etiology: Brain-biopsy diagnostic yields and safety

BackgroundFor nonneoplastic neurological diseases, no recommendation exists regarding the place or appropriate timing of brain biopsy. The aim of this study was to evaluate the diagnostic yield and safety of brain biopsies from patients with neurological diseases of unknown etiology. MethodsWe performed a retrospective cohort study from January 1, 2008 to December 31, 2018. We analyzed 1847 brain-biopsied patients, including 178 biopsies indicated for neurological diseases of unknown etiology. Specific histological and final diagnosis rates, positive diagnosis-associated factors, complication rate and complication-associated factors were assessed. ResultsSpecific histological diagnosis and final diagnosis rates were 71.3% and 83.1%, respectively, leading to therapeutic management change(s) for 75.3% of patients. Brain- biopsy–related mortality and permanent neurological morbidity occurred in 1.1% and 0.6% of the patients, respectively. The multivariable logistic-regression model retained (odds ratio [95% CI] only immunodepression (2.2 [1.1–4.7]; P=.04) as being independently associated with specific histological diagnosis, while supratentorial biopsy-targeted lesions (4.1 [1.1–15.2]; P=.04) were independently associated with a final diagnosis. Biopsies obtained from comatose patients were less contributive to the diagnosis (0.2 [0.05–0.7]; P=.01). Prebiopsy platelet count <100 G/L (28.5 [1.8–447]; P=.02), hydrocephalus (6.3 [1.2–15.3]; P=.02) and targeted lesions <1 cm (4.3 [1.2–15.3]; P=.03) were independently associated with brain biopsy-related complications. ConclusionFor highly selected patients with neurological diseases of unknown etiology, brain biopsy has a high diagnostic yield and low frequency of severe complications. We advocate that this procedure be considered early in the diagnosis algorithm of these patients.

No Definite Evidence for Human Endogenous Retroviral HERV-W and HERV-H RNAS in Plasma of Latvian Patients Suffering from Multiple Sclerosis and Other Neurological Diseases / Nav Apstiprinošu Pierādījumu Par Endogēno Retrovīrusu HERV-W Un HERV-H Rns Sastopamību Latvijas Pacientu Ar Multiplo Sklerozi Un Citām NeiroloĢiskām Slimībām Asins Plazmā

Abstract Multiple sclerosis (MS) is a neurological disease of unknown aetiology. Several research groups reported an increased level of human endogenous retroviruses HERV-W and HERV-H RNAs in cerebrospinal fluid, plasma and supernatants of cell cultures from MS individuals. To quantify the abundance of extracellular virion-associated HERV, RNAs in blood, plasma samples from Latvian MS patients, patients with other neurological diseases (OND), as well as blood donors (BD), were retrospectively studied by using both our previously published and newly developed quantitative Real-time reverse transcription PCR assays (QPCRs) targeting different polymerase (pol) gene regions of HERV-W and HERV-H. Unspecific signals due to incomplete removal of DNA were monitored by running the assays with and without reverse transcription (RT±) in parallel. According to our score, a few MS, OND and healthy controls gave borderline signals simultaneously with both newly developed HERV-H and HERV-W QPCRs, but the rest were negative. All borderline positive samples also had small amounts of non-retroviral cellular mRNA with possible origin from cell-free circulating RNA fragments, apoptotic bodies or exosomes, which can mimic the previously described virus-like particles. The results do not confirm the previous reports on prevalence of HERV-H or -W virion-associated RNA in plasma of MS patients.

Diagnostic Value and Safety of Brain Biopsy in Patients With Cryptogenic Neurological Disease: A Systematic Review and Meta-analysis of 831 Cases.

The role of brain biopsy in patients with cryptogenic neurological disease is uncertain. To determine the risks and benefits of diagnostic brain biopsy for nonneoplastic indications in immunocompetent patients. Appropriate studies were identified by searching electronic databases. We screened 3645 abstracts and included 20 studies with a total of 831 patients. Indications for biopsy were: (1a) severe neurological disease of unknown etiology in adults (n = 7) and (1b) in children (n = 2); (2) suspected primary angiitis of the central nervous system (PACNS) (n = 3); (3) chronic meningitis of unknown cause (n = 3); (4) atypical dementia (n = 4); and (5) nonneoplastic disease (n = 1). Diagnostic success rates calculated for subgroups were 51.3% (34.5-68.1) for 1a, 53.8% (42.9-64.5) for 1b, 74.7% (64.0-84.1) for 2, 30.3% (17.2-45.4) for 3, and 60.8% (41.2-78.8) for 4. Clinical impact rates were 30.5% (13.6-50.6) for 1a (n = 6), 67.1% (42.8-87.3) for 1b (n = 2), 8.3% (2.3-20.0) for 3 (n = 1), and 14.2% (6.5-24.3) for 4 (n = 2). Lymphoma (n = 32) and Creutzfeldt-Jakob disease (n = 30) were the most common diagnoses on the final histopathology reports of positive brain biopsies in 1a. In 1b, encephalitis (n = 7), PACNS (n = 6), and demyelination (n = 6) were the most common. The odds ratio for achieving a diagnostic biopsy when there was a radiological target was 3.70 (P = .014, 95% confidence interval, 1.31-10.42). Brain biopsy in cryptogenic neurological disease was associated with the highest diagnostic yield in patients with suspected PACNS. The greatest clinical impact was seen in children with cryptogenic neurological disease. The presence of a radiological target was associated with a higher diagnostic yield.

Novel Treatment with Neuroprotective and Antiviral Properties against a Neuroinvasive Human Respiratory Virus

Human coronaviruses (HCoVs) are recognized respiratory pathogens with neuroinvasive and neurotropic properties in mice and humans. HCoV strain OC43 (HCoV-OC43) can infect and persist in human neural cells and activate neuroinflammatory and neurodegenerative mechanisms, suggesting that it could be involved in neurological disease of unknown etiology in humans. Moreover, we have shown that HCoV-OC43 is neurovirulent in susceptible mice, causing encephalitis, and that a viral mutant with a single point mutation in the viral surface spike (S) protein induces a paralytic disease that involves glutamate excitotoxicity in susceptible mice. Herein, we show that glutamate recycling via the glial transporter 1 protein transporter and glutamine synthetase are central to the dysregulation of glutamate homeostasis and development of motor dysfunctions and paralytic disease in HCoV-OC43-infected mice. Moreover, memantine, an N-methyl-d-aspartate receptor antagonist widely used in the treatment of neurological diseases in humans, improved clinical scores related to paralytic disease and motor disabilities by partially restoring the physiological neurofilament phosphorylation state in virus-infected mice. Interestingly, memantine attenuated mortality rates and body weight loss and reduced HCoV-OC43 replication in the central nervous system in a dose-dependent manner. This novel action of memantine on viral replication strongly suggests that it could be used as an antiviral agent to directly limit viral replication while improving neurological symptoms in various neurological diseases with a viral involvement. Mutations in the surface spike (S) protein of human respiratory coronavirus OC43 appear after persistent infection of human cells of the central nervous system, a possible viral adaptation to this environment. Furthermore, a single amino acid change in the viral S protein modulated virus-induced neuropathology in mice from an encephalitis to a neuropathology characterized by flaccid paralysis, which involves glutamate excitotoxicity. We now show that memantine, a drug that is used for alleviating symptoms associated with neuropathology, such as Alzheimer's disease, can partially restore the physiological state of infected mice by limiting both neurodegeneration and viral replication. This suggests that memantine could be used as an antiviral agent while improving neurological symptoms in various neurological diseases with a viral involvement.

Acquired equine polyneuropathy in Norway and Sweden: A clinical and epidemiological study

Acquired equine polyneuropathy (AEP, also known as 'Scandinavian knuckling syndrome'), is a serious disease of unknown aetiology, which emerged clustering in horse farms in Sweden, Norway and Finland in the 1990s. Clinical and epidemiological data regarding the syndrome are scarce. To describe the clinical and epidemiological findings and outcome in outbreaks of AEP and compare risk factors in affected and unaffected horses on affected farms in Norway and Sweden during 2007-2009. Neurological examinations were performed and data collected regarding demography, usage, turning-out, feeding, prophylactic strategies and long-term outcome. Thirteen affected farms with 157 horses of various breeds, of which 42 were AEP cases, were studied. Typical digital extensor dysfunction and knuckling of pelvic limbs were noted in 34 definitive cases. Eight additional plausible cases had a severe, acute course of neurological disease. There were no signs of brain orcranial nerve dysfunction. Cases occurred from December to April, with new cases emerging within 100 days of the index case. Affected and unaffected horses were fed wrapped forage. Prevalence for AEP was 27% and case fatality 29%. The median duration of AEP in survivors was 4.4 months (1-17 months). Survivors returned to full work within 19 months (median 6.6 months). Acquired equine polyneuropathy was less prevalent in horses aged > 12 years and young horses had a higher chance of survival than older horses. Management factors did not differ between affected and unaffected horses. Acquired equine polyneuropathy is a potentially fatal neurological disease characterised by pelvic limb knuckling. Surviving horses returned to normal function after a long period of rest. Cases were clustered in farms during the winter/spring season. Wrapped forage was used in all farms. The results provide valuable insights into the dinical examination, handling and prognosis of cases of AEP, an emerging neurological disease of unknown aetiology in horses.

Orthostatic Tremor Inducing Instability

Orthostatic tremor (OT) is a neurological disease of unknown aetiology. It is defined by the presence of a 10–20Hz tremor in the legs while standing still. Symptoms described are dizziness and instability that diminish if the patient sits down or leans on something; drinking small amounts of alcohol significantly reduces OT. Due to the dizziness and/or unsteadiness, these patients are usually referred to the neuro-otology department. We report 4 cases diagnosed with OT. The diagnosis of OT should be considered for patients with instability. The clinical history is a key factor to suspect this entity, and the diagnosis is given by the register of 10–20Hz contractions on limb electromyography. Treatment for this disease consists of medical treatment; the first option is clonazepam.

Anesthetic Management of a Case with Moebius Syndrome

ABSTRACT Moebius syndrome is neurological disease of unknown etiology which is characterized by bilateral and unilateral facial and abducens nerve congenital paralysis. This syndrome usually presents with intubation difficulty due to the craniofacial anomaly and surgical interventions are required for treatment of inadequate chewing, swallowing, coughing reflex and hypotonicity, aspiration and respiratory problems. The aim of this case report is to present anesthesia technique during the extraction of 19 tooth in 2.5-year-old girl with severe hypotonia and possible difficult intubation due to craniofacial anomaly. How to cite this article Arpaci H, Kadioglu MN, Tuzuner-Oncul AM. Anesthetic Management of a Case with Moebius Syndrome. Int J Exper Dent Sci, 2012;1(1):37-39.

Temblor ortostático como causa de inestabilidad

Orthostatic tremor (OT) is a neurological disease of unknown aetiology. It is defined by the presence of a 10-20Hz tremor in the legs while standing still. Symptoms described are dizziness and instability that diminish if the patient sits down or leans on something; drinking small amounts of alcohol significantly reduces OT. Due to the dizziness and/or unsteadiness, these patients are usually referred to the neuro-otology department. We report 4 cases diagnosed with OT. The diagnosis of OT should be considered for patients with instability. The clinical history is a key factor to suspect this entity, and the diagnosis is given by the register of 10-20Hz contractions on limb electromyography. Treatment for this disease consists of medical treatment; the first option is clonazepam.

The Most Cited Parkinson's Disease Researchers – A Personal Perspective

As the inaugural issue of Journal of Parkinson’s Disease (www.journalofparkinsonsdisease.com) features an article highlighting the most cited 100 Parkinson’s disease researchers over the past 26 years and so many of them were based in or passed through the Maudsley and King’s College Hospitals in Denmark Hill and the National Hospital, Queen Square, in London while I was there, the editors suggested that I write a short piece about the transformation of “Parkinsonology” from that perspective and the contributions of some of those individuals. Sadly there is not enough space to mention all of the many other people who passed through, or collaborated, and also made significant contributions. Developments over the last 50 years or so have transformed the study of Parkinson’s disease from a relatively obscure untreatable neurological disease of unknown aetiology into a thriving modern neuroscience discipline involving specialist clinics and nurses, sophisticated clinical trials, dedicated brain banks, structural and functional imaging, genetic discoveries, animal models, patient and professional societies, and specialist journals, now including this new addition. We now have a much greater understanding of underlying mechanisms that paves the way to developing a second generation of strategies and therapies designed to modify the disease itself, and hopefully even to prevent it. The most cited 100 researchers have played an important part in this transformation.

Neurobrucellosis Associated with Syndrome of Inappropriate Antidiuretic Hormone with Resultant Diabetes Insipidus and Hypothyroidism

Neurological involvement of the central nervous system in brucellosis is uncommon. We describe a rare case of meningoencephalitis due to Brucella melitensis infection, associated with the syndrome of inappropriate antidiuretic hormone secretion and leading to diabetes insipidus and hypothyroidism. Neurobrucellosis, although rare, should be considered in cases of neurological disease of unknown etiology.

An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome)

A particularly important family of antioxidant defence enzymes in the body are the glutathione peroxidases, which remove H 2O 2 by coupling its reduction to H 2O with oxidation of reduced glutathione (GSH) to oxidised glutathione (GSSG). There are suggestions that GSH in the peripheral blood may be reduced in myalgic encephalomyelitis, which is a highly disabling neurological disease of unknown aetiology. Since many of the symptoms relate to cerebral functioning, it would seem probable that peripheral blood GSH findings would be reflected in lower cerebral GSH levels. The aim of this study was to carry out the first direct assessment of cerebral GSH levels in myalgic encephalomyelitis; the hypothesis being tested was that cerebral GSH levels would be reduced in myalgic encephalomyelitis. Cerebral proton neurospectroscopy was carried out at a magnetic field strength of 3 T in 26 subjects; spectra were obtained from 20×20×20 mm 3 voxels using a point-resolved spectroscopy pulse sequence. The mean cerebral GSH level in the myalgic encephalomyelitis patients was 2.703 (SD 2.311) which did not differ significantly from that in age- and gender-matched normal controls who did not have any history of neurological or other major medical disorder (5.191, SD 8.984; NS). Therefore our study does not suggest that GSH is reduced in the brain in myalgic encephalomyelitis. At the present time, based on the results of this study, there is no evidence to support the suggestion that, by taking glutathione supplements, an improvement in the brain-related symptomatology of myalgic encephalomyelitis may occur.

Gluten Sensitivity in Multiple Sclerosis

Patients with neurological disease of unknown etiology sometimes present with antigliadin and antitissue transglutaminase antibodies. The association between these antibodies and multiple sclerosis has been previously suggested. The purpose of this study was to determine the prevalence of these antibodies in multiple sclerosis patients. We determined the level of serum immunoglobulin A and immunoglobulin G antigliadin and antitissue transglutaminase antibodies in 98 patients with multiple sclerosis. We found a highly significant increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase in the multiple sclerosis patients. Seven patients had a positive IgG AGA, whereas only 2 controls presented positive titers (P = 0.03). Four patients had positive IgG anti-tTG while all the controls tested negative (P = 0.02). However, immunoglobulin A antibodies against gliadin and tissue transglutaminase were not statistically higher in the multiple sclerosis group in comparison to the control group. Our findings support the associations between antibodies against gliadin and tissue transglutaminase to multiple sclerosis. The specific role of these antibodies in the pathogenesis of multiple sclerosis remains uncertain and requires additional research. A gluten free diet should be considered in specific cases of patients who present with gluten antibodies.

Analysis of the Neuroinflammatory Response to TLR7 Stimulation in the Brain: Comparison of Multiple TLR7 and/or TLR8 Agonists

Activation of astrocytes and microglia and the production of proinflammatory cytokines and chemokines are often associated with virus infection in the CNS as well as a number of neurological diseases of unknown etiology. These inflammatory responses may be initiated by recognition of pathogen-associated molecular patterns (PAMPs) that stimulate TLRs. TLR7 and TLR8 were identified as eliciting antiviral effects when stimulated by viral ssRNA. In the present study, we examined the potential of TLR7 and/or TLR8 agonists to induce glial activation and neuroinflammation in the CNS by intracerebroventricular inoculation of TLR7 and/or TLR8 agonists in newborn mice. The TLR7 agonist imiquimod induced astrocyte activation and up-regulation of proinflammatory cytokines and chemokines, including IFN-beta, TNF, CCL2, and CXCL10. However, these responses were only of short duration when compared with responses induced by the TLR4 agonist LPS. Interestingly, some of the TLR7 and/or TLR8 agonists differed in their ability to activate glial cells as evidenced by their ability to induce cytokine and chemokine expression both in vivo and in vitro. Thus, TLR7 stimulation can induce neuroinflammatory responses in the brain, but individual TLR7 agonists may differ in their ability to stimulate cells of the CNS.

CD24 is a genetic modifier for risk and progression of multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24a) with valine (CD24v) in the mature protein. We found that the CD24v/v renders a >2-fold increase in the relative risk of MS in the general population (P = 0.023). Among familial MS, the CD24v allele is preferentially transmitted into affected individuals (P = 0.017). Furthermore, 50% of CD24v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24a/v (P = 0.00037) and CD24a/a (P = 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24a/a patients. Transfection with CD24a and CD24v cDNA demonstrated that the CD24v allele can be expressed at higher efficiency than the CD24a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.

The diagnosis of multiple sclerosis: Peplau's Interpersonal Relations Model in practice.

Multiple sclerosis (MS) is a chronic, frequently progressive neurological disease of unknown etiology and uncertain trajectory. Physicians and nurses have historically been uncomfortable broaching the topic of a possible MS diagnosis with patients and have tended instead to talk about it in euphemistic terms. However, with the development of therapeutic agents that may be more effective early in the disease course, the early communication of diagnostic and treatment information has become increasingly important. In our MS clinic, individual with MS symptoms are rapidly referred and assessed by a team of experienced physicians and nurses. Our experience with this referral process has led to our adoption of Peplau's Interpersonal Relations Model as a guide to nursing practice. The central element of Peplau's model is the development of a therapeutic relationship between patient and nurse. This relationship develops through four overlapping stages: orientation, identification, exploitation, and resolution. The collaborative relationship that develops between nurse and patient enhances problem solving and creates a strong bond that is essential across the long trajectory of the illness.

Multiple sclerosis: a geographical hypothesis

Multiple sclerosis remains a rare neurological disease of unknown aetiology, with a unique distribution, both geographically and historically. Rare in equatorial regions, it becomes increasingly common in higher latitudes; historically, it was first clinically recognized in the early nineteenth century. A hypothesis, based on geographical reasoning, is here proposed: that the disease is the result of a specific vitamin deficiency. Different individuals suffer the deficiency in separate and often unique ways. Evidence to support the hypothesis exists in cultural considerations, in the global distribution of the disease, and in its historical prevalence.

Survival Prediction in Sporadic Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive neurological disease of unknown etiology and fatal outcome. Patient management can be aided by careful assessment of prognostic factors. A prospective study of 158 patients was carried out to examine the prognostic significance of age and clinical form at onset. The overall 5-year survival rate was 14.7%. The higher the age was at first symptoms, the worse the prognosis. The bulbar and common forms had a worse prognosis than the pseudo-polyneuritic forms. After adjustment for age, the clinical form at onset remained a prognostic factor. In a multivariate analysis using the Cox model, these two factors remained independent despite the later onset of the bulbar forms. In view of the discrepancies between the different published studies, the evaluation of the survival of an individual patient is of doubtful value.