Ubiquitous neurocognitive dysfunction in familial adenomatous polyposis: proof-of-concept of the role of APC protein in neurocognitive function.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC gene. Patients with FAP have multiple extraintestinal manifestations that follow a genotype-phenotype pattern; however, few data exist characterizing their cognitive abilities. Given the role of the APC protein in development of the central nervous system, we hypothesized that patients with FAP would show differences in cognitive functioning compared to controls. METHODS: Matched case-control study designed to evaluate cognitive function using the Test of Nonverbal Intelligence-4, the Bateria III Woodcock-Munoz, and the Behavior Rating Inventory of Executive Functions-Adult. Twenty-six individuals with FAP (mean age = 34.2 ± 15.0 years) and 25 age-gender and educational level matched controls (mean age = 32.7 ± 13.8 years) were evaluated. RESULTS: FAP-cases had significantly lower IQ (p = 0.005). Across all tasks of the Batería III Woodcock-Muñoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls (p < 0.0001). Patients with FAP scored within the deficient range for Long-Term Retrieval and Cognitive Fluency. CONCLUSION: APC protein has an important role in neurocognitive function. The pervasive nature of the observed cognitive dysfunction suggests that loss or dysfunction of the APC protein impacts processes in cortical and subcortical brain regions. Additional studies examining larger ethnically diverse cohorts with FAP are warranted.

The Research Centers in Minority Institutions (RCMI) Translational Research Network: Building and Sustaining Capacity for Multi-Site Basic Biomedical, Clinical and Behavioral Research.

The Research Centers in Minority Institutions (RCMI) program was established by the US Congress to support the development of biomedical research infrastructure at minority-serving institutions granting doctoral degrees in the health professions or in a health-related science. RCMI institutions also conduct research on diseases that disproportionately affect racial and ethnic minorities (ie, African Americans/Blacks, American Indians and Alaska Natives, Hispanics, Native Hawaiians and Other Pacific Islanders), those of low socioeconomic status, and rural persons. Quantitative metrics, including the numbers of doctoral science degrees granted to underrepresented students, NIH peer-reviewed research funding, peer-reviewed publications, and numbers of racial and ethnic minorities participating in sponsored research, demonstrate that RCMI grantee institutions have made substantial progress toward the intent of the Congressional legislation, as well as the NIH/NIMHD-linked goals of addressing workforce diversity and health disparities. Despite this progress, nationally, many challenges remain, including persistent disparities in research and career development awards to minority investigators. The continuing underrepresentation of minority investigators in NIH-sponsored research across multiple disease areas is of concern, in the face of unrelenting national health inequities. With the collaborative network support by the RCMI Translational Research Network (RTRN), the RCMI community is uniquely positioned to address these challenges through its community engagement and strategic partnerships with non-RCMI institutions. Funding agencies can play an important role by incentivizing such collaborations, and incorporating metrics for research funding that address underrepresented populations, workforce diversity and health equity.

Implementation and Evaluation of Guillain-Barré Syndrome Surveillance in Puerto Rico during the 2016 Zika Virus Epidemic.

OBJECTIVE: Guillain-Barré syndrome (GBS) is an uncommon autoimmune disorder that follows infection or vaccination, and increased incidence has been reported during Zika virus (ZIKV) transmission. During the 2016 ZIKV epidemic, the Puerto Rico Department of Health (PRDH) implemented the Enhanced GBS Surveillance System (EGBSSS). Here, we describe EGBSSS implementation and evaluate completeness, validity, and timeliness. METHODS: GBS cases were identified using passive surveillance and discharge diagnostic code for GBS. Completeness was evaluated by capture-recapture methods. Sensitivity and positive predictive value (PPV) for confirmed GBS cases were calculated for both case identification methods. Median time to completion of key time steps were compared by quarter (Q1-4) and hospital size. RESULTS: A total of 122 confirmed GBS cases with onset of neurologic illness in 2016 were identified. Capture-recapture methodology estimated that four confirmed GBS cases were missed by both identification methods. Identification of cases by diagnostic code had a higher sensitivity than passive surveillance (89% vs. 80%), but a lower PPV (60% vs. 72%). There was a significant decrease from Q1 to Q3 in median time from hospital admission to case reporting (11 days vs. 2 days, p = 0.032) and from Q2 to Q3 in median time from specimen receipt to arbovirus laboratory test reporting (35 days vs. 26 days, p = 0.004). CONCLUSION: EGBSSS provided complete, valid, and increasingly timely surveillance data, which guided public health action and supported healthcare providers during the ZIKV epidemic. This evaluation provides programmatic lessons for GBS surveillance and emergency response surveillance.

Clinical Features of Guillain-Barré Syndrome With vs Without Zika Virus Infection, Puerto Rico, 2016.

Importance: The pathophysiologic mechanisms of Guillain-Barré syndrome (GBS) associated with Zika virus (ZIKV) infection may be indicated by differences in clinical features. Objective: To identify specific clinical features of GBS associated with ZIKV infection. Design, Setting, and Participants: During the ZIKV epidemic in Puerto Rico, prospective and retrospective strategies were used to identify patients with GBS who had neurologic illness onset in 2016 and were hospitalized at all 57 nonspecialized hospitals and 2 rehabilitation centers in Puerto Rico. Guillain-Barré syndrome diagnosis was confirmed via medical record review using the Brighton Collaboration criteria. Specimens (serum, urine, cerebrospinal fluid, and saliva) from patients with GBS were tested for evidence of ZIKV infection by real-time reverse transcriptase-polymerase chain reaction; serum and cerebrospinal fluid were also tested by IgM enzyme-linked immunosorbent assay. In this analysis of public health surveillance data, a total of 123 confirmed GBS cases were identified, of which 107 had specimens submitted for testing; there were 71 patients with and 36 patients without evidence of ZIKV infection. Follow-up telephone interviews with patients were conducted 6 months after neurologic illness onset; 60 patients with and 27 patients without evidence of ZIKV infection participated. Main Outcomes and Measures: Acute and long-term clinical characteristics of GBS associated with ZIKV infection. Results: Of 123 patients with confirmed GBS, the median age was 54 years (age range, 4-88 years), and 68 patients (55.3%) were male. The following clinical features were more frequent among patients with GBS and evidence of ZIKV infection compared with patients with GBS without evidence of ZIKV infection: facial weakness (44 [62.0%] vs 10 [27.8%]; P < .001), dysphagia (38 [53.5%] vs 9 [25.0%]; P = .005), shortness of breath (33 [46.5%] vs 9 [25.0%]; P = .03), facial paresthesia (13 [18.3%] vs 1 [2.8%]; P = .03), elevated levels of protein in cerebrospinal fluid (49 [94.2%] vs 23 [71.9%]; P = .008), admission to the intensive care unit (47 [66.2%] vs 16 [44.4%]; P = .03), and required mechanical ventilation (22 [31.0%] vs 4 [11.1%]; P = .02). Six months after neurologic illness onset, patients with GBS and evidence of ZIKV infection more frequently reported having excessive or inadequate tearing (30 [53.6%] vs 6 [26.1%]; P = .03), difficulty drinking from a cup (10 [17.9%] vs 0; P = .03), and self-reported substantial pain (15 [27.3%] vs 1 [4.3%]; P = .03). Conclusions and Relevance: In this study, GBS associated with ZIKV infection was found to have higher morbidity during the acute phase and more frequent cranial neuropathy during acute neuropathy and 6 months afterward. Results indicate GBS pathophysiologic mechanisms that may be more common after ZIKV infection.

Incidence and clinical characteristics of Guillain-Barré syndrome before the introduction of Zika virus in Puerto Rico.

BACKGROUND: Zika virus has been associated with increases in Guillain-Barré syndrome (GBS) incidence. A GBS incidence estimation and clinical description was performed to assess baseline GBS epidemiology before the introduction of Zika virus in Puerto Rico. METHODS: Hospitalization administrative data from an island-wide insurance claims database and U.S. Census Bureau population estimates provided a crude GBS incidence for 2013. This estimate was adjusted using the proportion of GBS cases meeting Brighton criteria for confirmed GBS from nine reference hospitals. Characteristics of confirmed GBS cases in the same nine hospitals during 2012-2015 are described. RESULTS: A total of 136 GBS hospitalization claims were filed in 2013 (crude GBS incidence was 3.8 per 100,000 population). The adjusted GBS incidence was 1.7 per 100,000 population. Of 67 confirmed GBS cases during 2012-2015, 66% had an antecedent illness. Median time from antecedent illness to GBS onset was 7days. Most cases (67%) occurred during July-September. CONCLUSIONS: Puerto Rico's GBS incidence for 2013 was estimated using a combination of administrative data and medical records review; this method could be employed in other regions to monitor GBS incidence before and after the introduction of GBS infectious triggers.

Guillain-Barré Syndrome During Ongoing Zika Virus Transmission - Puerto Rico, January 1-July 31, 2016.

Guillain-Barré syndrome (GBS) is a postinfectious autoimmune disorder characterized by bilateral flaccid limb weakness attributable to peripheral nerve damage (1). Increased GBS incidence has been reported in countries with local transmission of Zika virus, a flavivirus transmitted primarily by certain Aedes species mosquitoes (2). In Puerto Rico, three arthropod-borne viruses (arboviruses) are currently circulating: Zika, dengue, and chikungunya. The first locally acquired Zika virus infection in Puerto Rico was reported in December 2015 (3). In February 2016, the Puerto Rico Department of Health (PRDH), with assistance from CDC, implemented the GBS Passive Surveillance System (GBPSS) to identify new cases of suspected GBS (4). Fifty-six suspected cases of GBS with onset of neurologic signs during January 1-July 31, 2016, were identified. Thirty-four (61%) patients had evidence of Zika virus or flavivirus infection; the median age of these patients was 55 years (range = 21-88 years), and 20 (59%) patients were female. These 34 patients were residents of seven of eight PRDH public health regions. All 34 patients were hospitalized and treated with intravenous immunoglobulin G (IVIg), the standard treatment for GBS; 21 (62%) required intensive care unit admission, including 12 (35%) who required endotracheal intubation and mechanical ventilation. One patient died of septic shock after treatment for GBS. Additionally, 26 cases of neurologic conditions other than GBS were reported through GBPSS, including seven (27%) in patients with evidence of Zika virus or flavivirus infection. Residents of and travelers to Puerto Rico and countries with active Zika virus transmission should follow recommendations for prevention of Zika virus infections.* Persons with signs or symptoms consistent with GBS should promptly seek medical attention. Health care providers in areas with ongoing local transmission seeing patients with neurologic illnesses should consider GBS and report suspected cases to public health authorities.

Local Transmission of Zika Virus--Puerto Rico, November 23, 2015-January 28, 2016.

Zika virus, a mosquito-borne flavivirus, spread to the Region of the Americas (Americas) in mid-2015, and appears to be related to congenital microcephaly and Guillain-Barré syndrome (1,2). On February 1, 2016, the World Health Organization (WHO) declared the occurrence of microcephaly cases in association with Zika virus infection to be a Public Health Emergency of International Concern.* On December 31, 2015, Puerto Rico Department of Health (PRDH) reported the first locally acquired (index) case of Zika virus disease in a jurisdiction of the United States in a patient from southeastern Puerto Rico. During November 23, 2015-January 28, 2016, passive and enhanced surveillance for Zika virus disease identified 30 laboratory-confirmed cases. Most (93%) patients resided in eastern Puerto Rico or the San Juan metropolitan area. The most frequently reported signs and symptoms were rash (77%), myalgia (77%), arthralgia (73%), and fever (73%). Three (10%) patients were hospitalized. One case occurred in a patient hospitalized for Guillain-Barré syndrome, and one occurred in a pregnant woman. Because the most common mosquito vector of Zika virus, Aedes aegypti, is present throughout Puerto Rico, Zika virus is expected to continue to spread across the island. The public health response in Puerto Rico is being coordinated by PRDH with assistance from CDC. Clinicians in Puerto Rico should report all cases of microcephaly, Guillain-Barré syndrome, and suspected Zika virus disease to PRDH. Other adverse reproductive outcomes, including fetal demise associated with Zika virus infection, should be reported to PRDH. To avoid infection with Zika virus, residents of and visitors to Puerto Rico, particularly pregnant women, should strictly follow steps to avoid mosquito bites, including wearing pants and long-sleeved shirts, using permethrin-treated clothing and gear, using an Environmental Protection Agency (EPA)-registered insect repellent, and ensuring that windows and doors have intact screens.

Epidermal innervation in healthy children and adolescents.

INTRODUCTION: Epidermal nerve fiber (ENF) density, morphology, and epidermal innervation patterns were examined in children using 2 different techniques, punch biopsy and suction blister. METHODS: Healthy children without symptoms or history of peripheral neuropathy and normal by neurologic examination were studied. Punch biopsy and suction blister specimens were collected from the lateral thigh and distal leg. ENFs were traced from confocal images of immunohistochemically stained samples. Statistical methods included repeated-measures analysis of covariance. RESULTS: Blister and biopsy nerve counts were associated. ENF density in children was dense, lower for older children (P<0.01) and with no difference between boys and girls (P=0.92). Many ENFs appeared multibranched and elongated. CONCLUSIONS: Epidermal innervation in the pediatric population is dense and age-dependent. Blister specimens are less invasive and may provide an alternative to punch biopsy for determining ENF density in children at risk for neuropathy.

Decoding pathogenesis of slow-channel congenital myasthenic syndromes using recombinant expression and mice models.

Despite the fact that they are orphan diseases, congenital myasthenic syndromes (CMS) challenge those who suffer from it by causing fatigable muscle weakness, in the most benign cases, to a progressive wasting of muscles that may sentence patients to a wheelchair or even death. Compared to other more common neurological diseases, CMS are rare. Nevertheless, extensive research in CMS is performed in laboratories such as ours. Among the diverse neuromuscular disorders of CMS, we are focusing in the slow-channel congenital myasthenic syndrome (SCS), which is caused by mutations in genes encoding acetylcholine receptor subunits. The study of SCS has evolved from clinical electrophysiological studies to in vitro expression systems and transgenic mice models. The present review evaluates the methodological approaches that are most commonly employed to assess synaptic impairment in SCS and also provides perspectives for new approaches. Electrophysiological methodologies typically employed by physicians to diagnose patients include electromyography, whereas patient muscle samples are used for intracellular recordings, single-channel recordings and toxin binding experiments. In vitro expression systems allow the study of a particular mutation without the need of patient intervention. Indeed, in vitro expression systems have usually been implicated in the development of therapeutic strategies such as quinidine- and fluoxetine-based treatments and, more recently, RNA interference. A breakthrough in the study of SCS has been the development of transgenic mice bearing the mutations that cause SCS. These transgenic mice models have actually been key in the elucidation of the pathogenesis of the SCS mutations by linking IP-3 receptors to calcium overloading, as well as caspases and calpains to the hallmark of SCS, namely endplate myopathy. Finally, we summarize our experiences with suspected SCS patients from a local perspective and comment on one aspect of the contribution of our group in the study of SCS.

Fatal granulomatous meningoencephalitis associated to mycobacterium mucogenicum-like microorganism: a case report.

Mycobacterium mucogenicum is rarely associated to human infections. However, in the last year, a few reports of sepsis and fatal cases of central nervous systems have been documented. Here we report a fatal case of granulomatous meningoencephalitis of three weeks of evolution where DNA from a M. mucogenicum-like microorganism was identified postmortem in samples of brain tissue.

Recent developments in the HIV neuropathies.

PURPOSE OF REVIEW: With the introduction of highly active antiretroviral therapy peripheral neuropathies have become the most common neurological complications in HIV infection. The frequency and spectrum of these neuropathies are changing, as the various toxic and immune factors are modified by new treatment strategies. Recent studies have provided a better understanding of the risk factors, markers and relevant pathogenic mechanisms, and a thorough review of these is critical for an improved understanding of this important and increasingly common complication. RECENT FINDINGS: The combined use of dideoxynucleosides, in association with immune-mediated mechanisms triggered by HIV infection, are critical in the development of distal sensory polyneuropathy. Valuable markers of neuropathy such as intraepidermal nerve fiber density from skin biopsies have been validated and promise to be a valuable tool in the detection and monitoring of distal sensory polyneuropathy. Markers of virological activity have also been associated with the severity of neuropathic pain in distal sensory polyneuropathy. In some instances, the enhanced viral suppression from antiretroviral agents may actually improve or decrease the frequency of certain types of neuropathy. New evidence supports mitochondrial toxicity as a principal mechanism for dideoxynucleoside-associated sensory neuropathy, and questions arise about enhanced risk with pre-existing mitochondrial defects. Confirmed treatments are limited to the reduction of symptoms, with a need for the further investigation of corrective therapies. SUMMARY: Increased and improved surveillance for HIV-associated neuropathy will allow earlier interventions to improve quality of life and prevent severe toxicities. A better understanding of the prevailing mechanisms will allow for more effective interventions.

Physiological characterization of neuropathy in Fabry's disease.

Fabry's disease is commonly associated with a painful, debilitating neuropathy. Characterization of the physiological abnormalities is an important step in evaluating response to specific therapies. Twenty-two patients with Fabry's disease, and with relatively preserved renal function, underwent conventional and near-nerve conduction studies, electromyography, sympathetic skin responses, and quantitative sensory testing (QST). Nerve conduction studies were mostly normal except for an increased frequency of median nerve entrapment at the wrist in 6 (27%) patients. Sympathetic skin responses were preserved in 19 of 20 (95%) of the patients. The QST showed increased or immeasurable cold and warm detection thresholds in patients, significantly different from controls (n = 28) in the hand (P < 0.001, P = 0.04, respectively) and foot (P < 0.001 for both). Cold thresholds were more often abnormal than were warm thresholds. Vibration thresholds were normal in the feet and, in some patients, elevated in the hand only, probably due to frequent median nerve entrapment at the wrist. Our findings suggest that the neuropathy of Fabry's disease is characterized by an increased prevalence of median nerve entrapment at the wrist and by thermal afferent fiber dysfunction in a length-dependent fashion, with greater impairment of cold than warm sensation.