Limbic encephalitis in a COVID-19 patient?

We describe the case of a 79-year-old woman infected by SARS-CoV-2 and purely neurological confusional syndrome without clinically relevant respiratory disease and NMR alterations of the limbic system.

Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.

The pathway leading from amyloid-ß deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1ß, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-α]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy-) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1ß) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = -9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy- (FC = -7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1ß, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = -0.48, p < 0.001; rho = -0.25, p = 0.024; rho = -0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.

Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

IMPORTANCE: Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE: To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS: Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE: Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Rhabdomyolysis in hyponatremia and paraneoplastic syndrome of inappropriate antidiuresis.

We report a 26-year-old woman admitted to our hospital for generalized tonic seizure. Laboratory investigations revealed severe hyponatremia possibly triggered by vomiting and diarrhea. 24 hours after correction of hyponatremia she developed diffuse myalgias and marked hyperCKemia. Syndrome of inappropriate antidiuresis (SIAD) was suspected as cause of hyponatremia. Abnormal vaginal bleeding prompts gynecological evaluation and a small-cell carcinoma of uterine cervix was detected.

Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear. OBJECTIVE: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment. DESIGN: Retrospective histochemical, biochemical, and molecular studies of muscle specimens. SETTING: Tertiary care university. Subjects Fifty patients with typical sporadic ALS (mean age, 55 years). Main Outcome Measure Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis. RESULTS: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis. CONCLUSIONS: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.

Absence of angiogenic genes modification in Italian ALS patients.

To investigate the role of vascular endothelial growth factor (VEGF) and angiogenin (ANG) as genetic determinants in the susceptibility to sporadic ALS in Italian patients. VEGF genotype and haplotype analysis revealed no association between any variants and the risk of ALS. Regarding ANG gene, no mutation was detected and the rs11701 polymorphism, previously described as associated with ALS, was not differently distributed between patients and controls. Overall, our data argue against the hypothesis of both genes as risk factors for motoneuron neurodegeneration, at least in an Italian population.

Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects.

Six years before the present study we performed a retrospective study of 114 subjects presenting with asymptomatic / oligosymptomatic hyperckemia (raised creatine kinase blood levels), a diagnosis being made in 21 of them. We now present the results of a long-term follow-up in 55 of the still undiagnosed 93 individuals. Most of them have remained asymptomatic and did not develop specific neuromuscular disorders. One subject became frankly symptomatic manifesting limb-girdle weakness. A diagnosis of dystrophinopathy carrier and one of possible type I SMA carrier were indirectly made in another two subjects. Almost all subjects still have hyperckemia, though the mean creatine kinase (CK) value is lower than before. CK levels have become normal in 12 subjects. Two died of neoplasia, and six developed non-neuromuscular disorders. We noted no follow-up differences in terms of CK modifications between subjects with pathological EMG and/or muscle biopsy findings and those with normal findings at first examination.

New mutations in TK2 gene associated with mitochondrial DNA depletion.

Mitochondrial deoxyribonucleic acid depletion syndromes are autosomal recessive disorders characterized by a reduction of the amount of mitochondrial deoxyribonucleic acid, which impairs the synthesis of respiratory chain complexes. Mutations in the deoxyguanosine kinase and polymerase gamma genes have been identified in hepatocerebral forms, whereas thymidine kinase 2 gene mutations have been found in patients with isolated myopathy, encephalomyopathy, or spinal muscular atrophy. Mutations in the gene encoding the beta subunit of the adenosine diphosphate-forming succinyl-coenzyme A synthetase have also been reported in a family. In this report, the clinical, molecular, morphologic, and biochemical features of five children from two independent families with an infantile encephalomyopathy are characterized. The affected children manifested muscle mitochondrial deoxyribonucleic acid depletion and three novel thymidine kinase 2 gene mutations. They consist of a homozygous substitution resulting in Ala to Val change at the highly conserved position 181 of thymidine kinase in the first family, and two heterozygous substitutions in the second family: a Cys to Trp change at residue 108 and a Leu to Pro change at residue 257 of the enzyme. Common clinical features associated with these TK2 mutations are a normal early developmental phase followed by psychomotor regression, encephalopathy often with epileptic seizures, and myopathy with features of a progressive dystrophic process.

Congenital muscular dystrophy with muscle inflammation alpha dystroglycan glycosylation defect and no mutation in FKRP gene.

Congenital muscular dystrophies (CMD) are autosomal recessive infantile disorders characterized by dystrophic changes at muscle biopsy and contractures. Central nervous system (CNS) abnormalities associated with mental retardation are often present. We describe a patient affected with muscle weakness, psychomotor developmental delay and normal brain MRI. Muscle biopsy showed complete absence of the alpha-dystroglycan (DG) glycosylated epitope and preservation of alpha-dystroglycan (alpha-DG) protein core. The analysis of FKRP, LARGE, POMT1 and POMGnT1 genes did not show any pathogenic mutations, suggesting that at least another gene may account for CMD with secondary glycosylated alpha-DG deficiency.

Muscle coenzyme Q10 level in statin-related myopathy.

BACKGROUND: Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle-related complaints. Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ10 concentration may have a role in the pathogenesis of statin drug-related myopathy. OBJECTIVES: To measure the CoQ10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug-related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) assay. DESIGN: An open-labeled study of CoQ10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy. SETTING: Neuromuscular centers at 2 academic tertiary care hospitals. RESULTS: Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients. CONCLUSION: These data suggest that statin drug-related myopathy is associated with a mild decrease in muscle CoQ10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.

Decorin and biglycan expression is differentially altered in several muscular dystrophies.

Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-beta1. We examined muscle biopsies from nine DMD patients, aged 2-8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1-5 years; five aged 30-37 years); four MDC1A patients (aged 2-7 years); six dysferlin-deficient patients (aged 19-53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 sarcoglycan-deficient patients: seven with alpha-sarcoglycan mutation, two with beta-sarcoglycan mutation and one with gamma-sarcoglycan mutation (five aged 8-15 years; five aged 26-43 years); and nine children (aged 1-6 years) and 12 adults (aged 16-61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-beta1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-beta1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.

A case of CPT deficiency, homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy.

A 45-year-old male patient had an episode of acute renal failure with myoglobinuria, myalgias, weakness, and markedly increased serum CK levels. Similar episodes had occurred in the past. Carnitine palmitoyl-transferase II (CPT II) deficiency was documented both biochemically and genetically. Interestingly, muscle biopsy also showed some ragged red fibers (RRF) and complete mitochondrial DNA (mtDNA) sequence disclosed a homoplasmic T3394C point mutation. This mutation is described in Leber's hereditary optic neuropathy (LHON) or in patients with diabetes mellitus.

High mutational burden in the mtDNA control region from aged muscles: a single-fiber study.

The ageing process is associated with the accumulation of somatic mutations of mitochondrial DNA (mtDNA). The aged human skeletal muscle tissue presents a mosaic of fibers when stained histochemically for cytochrome c oxidase (COX) activity with a proportion of COX negative fibers. Given the potential relevance of any alteration in the mtDNA control region for replication, we analysed the correlation between the presence of mutations and their degree of heteroplasmy and the COX phenotype in individual muscle fibers of aged healthy donors.A region of the mtDNA D-loop was cloned from single fiber-derived DNA and multiple clones were analysed. This strategy showed that a high level of mutational burden is present in all fibers and that several types of mtDNA rearrangements are detectable: recurrent (A189G, T408A and T414G) and rare point mutations, length variations affecting the homopolymeric tract and the (CA)(n) repeat and macrodeletions. The aggregate mutational load in the D-loop region correlated with the single fiber COX phenotype, suggesting that the cumulative burden of multiple, individually rare, mtDNA alterations might functionally impair the mitochondrial genetic machinery.

Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels.

UNLABELLED: A retrospective evaluation of asymptomatic subjects with persistent elevation of serum creatine kinase (CK) levels (hyperCKemia) was made in order to verify the presence of subclinical myopathy or idiopathic hyperCKemia and to define the most appropriate diagnostic pathway. Persistently increased serum CK levels are occasionally encountered in healthy individuals. In 1980 Rowland coined for them the term idiopathic hyperCKemia. Despite the increase of scientific knowledge, several healthy subjects with hyperCKemia still represent a problem for the clinician. We made a retrospective evaluation of 114 asymptomatic or minimally symptomatic individuals with incidentally detected persistent hyperCKemia. They underwent neurological examination and laboratory/instrumental evaluation. Skeletal muscle biopsy was performed and thoroughly investigated. Biochemical and genetic investigations were added in selected cases. Logistic regression analysis was applied. We diagnosed a neuromuscular disorder in 21 patients (18.4%), and found, by muscle biopsy and/or EMG, pathological but not conclusive findings in 57 subjects (50%). The statistic correlation between elevated serum CK levels and the probability of making a diagnosis changed according to the age of the patient. CONCLUSIONS: Muscle biopsy is the basic tool for screening asymptomatic subjects with hyperCKemia. It allowed us to make a diagnosis of disease in 18.4% of patients, and to detect skeletal muscle abnormalities in 38.6% of the subjects. Interestingly, 31.6% of individuals had completely normal muscle findings. These best fit the "diagnosis" of idiopathic hyperCKemia.