Markedly asymmetric presentation in multiple system atrophy

BackgroundMultiple system atrophy (MSA) presents with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement. Marked asymmetry in atypical parkinsonism suggests alternative diagnosis like Corticobasal syndrome (CBS).MethodsWe describe five unusual cases, who presented initially with markedly asymmetric parkinsonism, rigid dystonic abnormal limb posturing and subsequently developed clinical and/or radiological features consistent with probable MSA-P.ResultsUsing the internationally accepted diagnostic criteria, the patients fulfilled the diagnostic criteria for probable MSA-P after 5 years from disease onset. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed.ConclusionsWe use these cases to highlight that MSA-P MSA-P can present rarely with very marked asymmetry, dystonic limb and myoclonic jerks leading to a diagnosis of CBS at onset.     

Rapid eye movement sleep behavior disorder in treatment-naïve Parkinson disease patients

Objective

Rapid eye movement (REM) sleep behavior disorder (RBD) is a risk factor for dementia in Parkinson disease (PD) patients. The objectives of our study were to prospectively evaluate the frequency of RBD in a sample of treatment-naïve, newly diagnosed PD patients and compare sleep characteristics and cognition in RBD and non-RBD groups.

Methods

Fifty-seven newly diagnosed PD patients were consecutively recruited in a university medical center. All patients underwent two overnight polysomnography (PSG) sessions and were diagnosed with RBD according to the International Classification of Sleep Disorders, Second Revision criteria. Daytime sleepiness was measured in a multiple sleep latency test (MSLT). Cognition was assessed in a standard neuropsychologic examination.

Results

Seventeen PD patients (30%) met the criteria for RBD. The RBD patients and non-RBD patients did not significantly differ in mean age, gender ratio, disease duration, motor symptom subtype and severity, total sleep time, percentage of REM sleep, apnea–hypopnea index, mean oxygen saturation, and importantly cognitive performance. However, non-RBD patients had a significantly shorter mean daytime sleep latency than RBD patients (15 vs 18 min, respectively; P = .014).

Conclusion

A high frequency of RBD was found in our sample of 57 newly diagnosed PD patients. At this stage in the disease, RBD was not found to be associated with other sleep disorders or cognitive decline. Follow-up is needed to assess the risk for developing dementia in early-stage PD patients with RBD.     

Protection Against Type 1 Diabetes Upon Coxsackievirus B4 Infection and iNKT-Cell Stimulation: Role of Suppressive Macrophages

Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2–deficient NOD mice, the activation of iNKT cells by a specific agonist, α-galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes.Type 1 diabetes is characterized by the destruction of pancreatic islet β-cells by autoreactive CD4 and CD8 T cells, leading to low insulin production and incapacity to regulate blood glucose levels (1). Despite numerous studies, the etiology of type 1 diabetes remains elusive. Besides genetics (2–4), environmental factors such as viral infections have been suggested as triggers of type 1 diabetes (5–7). Most striking of these infections are the type B Coxsackieviruses belonging to the enterovirus genus whose genome and anti-Coxsackievirus antibodies were detected more frequently in the blood of recently diagnosed patients compared with healthy controls (8,9). Besides, enteroviral RNA or enteroviral particles were directly detected in the pancreas of type 1 diabetic patients, whereas they were undetectable in the pancreas of healthy donors (9,10). In a mouse model of type 1 diabetes, Serreze et al. (11) showed that diabetes can develop rapidly after Coxsackievirus B4 (CVB4) infection if mice had an advanced age and sufficient insulitis. Others have reported that inefficient islet β-cell response, viral dose, and replication rate as well as a lack of islet neogenesis could also promote accelerated diabetes development after CVB4 infection (12–14).Natural killer T (NKT) cells are CD1d-restricted, nonconventional T cells recognizing self and exogenous glycolipids. Most NKT cells express an invariant T-cell receptor α chain, Vα14-Jα18 (Vα14) in mice and Vα24-Jα18 in humans, and are named invariant NKT (iNKT) cells. They can promptly secrete copious amounts of interferon-γ (IFN-γ) and interleukin (IL)-4 and provide maturation signals to dendritic cells (DCs) and lymphocytes, thereby contributing to both innate and acquired immunity (15,16). iNKT cells are potent regulatory cells that can inhibit autoimmunity and promote immune responses against pathogens (1,17). Diabetes can be prevented in NOD mice by increasing iNKT cell numbers and by iNKT-cell stimulation with exogenous ligands such as α-galactosylceramide (αGalCer) (15,18,19). NOD mice protected from diabetes by iNKT cells have weak T helper 1 anti-islet β-cell responses (20). Indeed, iNKT cells can impair the differentiation of anti-islet CD4 and CD8 T cells, which become hyporesponsive or anergic (21). Contrary to their suppressive role in type 1 diabetes, iNKT cells can enhance immune responses to pathogens such as parasites, bacteria, and viruses (22,23).Our previous studies conducted in a murine model of type 1 diabetes with lymphocytic choriomeningitis virus infection revealed that iNKT cells could promote systemic antiviral CD8 T-cell responses while inhibiting deleterious anti-islet T-cell responses, thereby preventing type 1 diabetes (24,25). In the present study, we investigated the role of iNKT cells after CVB4 infection, revealing that diabetes development following CVB4 infection is associated with the infiltration of inflammatory macrophages into the pancreatic islets with subsequent activation of anti-islet T cells. However, the activation of iNKT cells during CVB4 infection results in the infiltration of suppressive macrophages into pancreatic islets. Indoleamine 2,3-dioxygenase (IDO) expressed by these macrophages was critical for the inhibition of diabetes development.     

Lexical spelling in children and adolescents with specific language impairment: Variations with the writing situation

The goal of this study was to compare the lexical spelling performance of children and adolescents with specific language impairment (SLI) in two contrasting writing situations: a dictation of isolated words (a classic evaluative situation) and a narrative of a personal event (a communicative situation). Twenty-four children with SLI and 48 typically developing children participated in the study, split into two age groups: 7–11 and 12–18 years of age. Although participants with SLI made more spelling errors per word than typically developing participants of the same chronological age, there was a smaller difference between the two groups in the narratives than in the dictations. Two of the findings are particularly noteworthy: (1) Between 12 and 18 years of age, in communicative narration, the number of spelling errors of the SLI group was not different from that of the typically developing group. (2) In communicative narration, the participants with SLI did not make specific spelling errors (phonologically unacceptable), contrary to what was shown in the dictation. From an educational perspective or that of a remediation program, it must be stressed that the communicative narration provides children—and especially adolescents—with SLI an opportunity to demonstrate their improved lexical spelling abilities. Furthermore, the results encourage long-term lexical spelling education, as adolescents with SLI continue to show improvement between 12 and 18 years of age.     

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.