Recessive distal motor neuropathy with pyramidal signs in an Omani kindred: underlying novel mutation in the SIGMAR1 gene.

BACKGROUND AND PURPOSE: Distal hereditary motor neuropathy (dHMN) due to sigma non-opioid intracellular receptor 1 (SIGMAR1) gene mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co-existing pyramidal signs initially described in a Chinese family recently. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of SIGMAR1 mutations. METHODS: We utilized homozygosity mapping and whole-exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length-dependent motor neuropathy and pyramidal signs. RESULTS: We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of the SIGMAR1 gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling who carried, at most, a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), probably flagging the mRNA for nonsense-mediated decay leading to a complete loss of function, thereby potentially contributing to the disease process. CONCLUSIONS: Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is pan-ethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co-existing pyramidal signs and autosomal recessive inheritance.

Full Outline of UnResponsiveness score and Glasgow Coma Scale in medical patients with altered sensorium: interrater reliability and relation to outcome.

PURPOSE: Full Outline of UnResponsiveness, or FOUR score (FS), is a recently described scoring system for evaluation of altered sensorium. This study examined interrater reliability for FS and Glasgow Coma Scale (GCS) among medical patients with altered mental status and compared outcome predictability of GCS, FS, and Sequential Organ Failure Assessment score. PATIENTS AND METHODS: Adult patients with altered mental status due to medical causes were rated by neurology consultants and internal medicine residents on FS and GCS. Interobserver reliability for GCS and FS was assessed using κ score. Relation with outcomes was explored using univariate and multivariate analyses. MAIN RESULTS: Of the 100 patients (age, 62 ± 17 years), 60 had neurologic conditions; 26, metabolic encephalopathy; 9, infections; and 7, others. Thirty-nine patients died at 3 months. κ Scores ranged from 0.71 to 0.85 for GCS and from 0.71 to 0.95 for FS. On multivariate analysis, GCS was predictive of outcome at 3 months; FS was predictive of mortality. Area under the receiver operating characteristic curves suggested equivalent performance of both scoring systems. CONCLUSIONS: Interrater reliability and outcome predictability for FS were comparable with those for GCS. This study supports the use of FS for evaluation of altered mental status in the medical wards.

Acute drug overdose: clinical profile, etiologic spectrum and determinants of duration of intensive medical treatment.

OBJECTIVES: Acute drug overdosing is an important cause of organ dysfunction and metabolic derangements and the patients often require intensive care. This study aims to determine the clinical pattern of severe drug overdose as well as the factors influencing the duration of intensive care METHODS: The clinical characteristics and course of consecutive adult patients admitted with a diagnosis of acute drug poisoning in the ICU of a tertiary hospital in Oman from January 2007 to December 2008 were reviewed retrospectively from the electronic case records. RESULTS: Acute drug poisoning (n=29) constituted 3.9% of admissions to the ICU. Mean age was 29.38±7.9 years. They were brought in by their relatives (72%) or the state services (24%). Accidental poisoning was noted in 21 patients (72%) and suicidal overdosing in 6 (21%). The commonest drug was an opioid (65.5%). Glasgow Coma Scale score of ≤8 was recorded in 18 (62.1%). Sixty two percent of patients required mechanical ventilation. The prominent complications were hypotension in 9 (31%), pulmonary in 19 (65.5%), hepatic in 18 (62.1%) and renal in 12 (41.4%) patients. The major electrolytes abnormalities were low bicarbonate in 11 (37.9%), hyponatremia in 5 (17.2%) and hypokalemia in 4 (13.8%). Patients stayed in the ICU for 1 to 20 days (median-2 days). Factors associated with a longer ICU stay included hypotension upon arrival (p=0.048) and the need for mechanical ventilation on the first (p=0.001) and second (p=0.001) days of hospitalization. There was no mortality. CONCLUSION: Early and prompt intensive medical therapy in acute drug poisoning can favorably influence the outcome. In addition, the presence of hypotension and requirement of mechanical ventilation on the first two days of hospitalization were responsible for prolonged ICU stay.

Response to heat pain stimulation in idiopathic Parkinson's disease.

BACKGROUND: Pain is a prominent nonmotor symptom in Parkinson's disease (PD) but has not been well studied. OBJECTIVE: The aim of this study is to assess thermal experience and emotional content, as well as side-to-side sensory differences in PD "off" and "on" dopaminergic therapy following thermal cutaneous stimulation. DESIGN: Cross-sectional design. SETTING: University teaching hospital. METHODS: Twelve PD subjects experiencing motor fluctuations but no pain symptoms and 13 healthy controls participated in the study. Heat pain and emotional content were assessed using a thermode and visual analog scales in medication on and off states in PD and without medication in healthy controls. RESULTS: There were no side to side differences in heat pain intensity or between PD medication on state and PD medication off state. Unexpectedly, PD subjects reported a higher degree of unpleasantness in response to heat pain while on medication compared with the off state. CONCLUSIONS: These results suggest that the perception of heat pain is mediated, at least in part, by nondopaminergic systems in PD, while dopamine might modulate the affective component of pain.

Neuromyelitis optica: an overview.

Neuromyelitis optica (NMO) is a relapsing inflammatory disorder of the central nervous system that closely resembles multiple sclerosis. This review discusses recent understanding of NMO with reference to epidemiology, clinical spectrum, immunopathology, diagnostic evaluation, clinical course and management. Within the clinical spectrum of NMO, the classical form (with relapsing opticomyelitis) and limited forms (either recurrent myelitis or optic neuritis), as well as its association with other autoimmune disorders, have been recognised in recent years. Further, symptomatic or asymptomatic cerebral lesions may be present, and such brain lesions do not necessarily exclude the diagnosis. In the appropriate clinical context, the diagnosis is supported by longitudinally extensive myelitis on spinal MRI. Overwhelming evidence strongly indicates that aquaporin 4 antibody has a pathogenetic role in the development of NMO and serves as a useful diagnostic and prognostic marker. Detection of this autoantibody has led to the categorisation of NMO as an autoimmune channelopathy. NMO can be distinguished from multiple sclerosis by a combination of clinical, radiological and laboratory studies. However, the nosological position of Asian opticospinal multiple sclerosis is not settled. In NMO, acute attacks usually result in moderate to severe functional impairment, and, in the absence of a secondary progressive course (unlike relapsing-remitting multiple sclerosis), prevention of relapses is of crucial importance in the management of the disease. Indeed, relapse prevention with long-term immunosuppressive medication remains the cornerstone of therapy in this otherwise debilitating disease!

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study.

Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Progression of dopaminergic dysfunction in a LRRK2 kindred: a multitracer PET study.

OBJECTIVE: Little is known about the progression of dopaminergic dysfunction in LRRK2-associated Parkinson disease (PD). We sought to characterize the neurochemical progression with multitracer PET in asymptomatic members of parkinsonian kindred (family D, Western Nebraska) carrying LRRK2 (R1441C) mutation. METHOD: Thirteen family D subjects underwent PET scans of presynaptic dopaminergic integrity and five subjects were rescanned 2 to 3 years later. RESULTS: In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of decline in healthy controls. Reduced dopamine transporter binding was the earliest indication of subclinical dopaminergic dysfunction and progression to clinical disease was generally associated with the emergence of abnormal fluorodopa uptake. CONCLUSION: PET study of presymptomatic members of our LRRK2 kindred revealed dopaminergic dysfunction that progressed over time. This represents an ideal group to study the natural history of early disease and the potential effects of neuroprotective interventions.

Functional imaging in Parkinson disease.

OBJECTIVE: Functional imaging techniques represent useful tools to assess in vivo the neurochemical alterations and functional connectivity in Parkinson disease (PD). Here, the authors review the various approaches and potential application of these imaging techniques to the study of PD. METHOD: Radiotracer imaging using dopaminergic markers facilitates assessment of pre- and postsynaptic nigrostriatal integrity, while imaging with other appropriate radiotracers explores nondopaminergic neurotransmitter function, local metabolism, blood flow, and mechanisms potentially related to disease progression and pathogenesis. Activation studies using functional MRI detect blood oxygen level dependent signal, as an indirect marker of neuronal activity. RESULT: Functional imaging techniques have been applied to infer the potential role of inflammation and other factors in etiopathogenesis as well as to study compensatory and regulatory mechanisms in early PD and subclinical disease in genetic forms of PD. Imaging studies also help to understand the neurobiological basis of motor and nonmotor complications. Recent reports suggest a role for striatal dopaminergic transmission in modulating neurobehavioral processes including the placebo effect in PD. Although functional imaging has been employed to monitor disease progression, the discordance between clinical outcome and imaging measures after therapeutic interventions precludes their use as surrogate end points in clinical trials. Beyond these limitations and potential challenges, imaging techniques continue to find wide application in the study of PD. CONCLUSION: Functional imaging can provide meaningful insights into mechanisms underlying various aspects of motor and nonmotor dysfunction in Parkinson disease and the role of striatal dopaminergic transmission in behavioral processes beyond motor control. These modalities hold promise to study the preclinical phase and to elucidate further the benefits and complications of surgical interventions and the utility of neuroprotective strategies.

Generalised convulsive status epilepticus: an overview.

Generalised convulsive status epilepticus is one of the most common emergencies encountered in clinical practice. This review discusses the recent understanding of this life-threatening condition with reference to the definition, pathophysiology, evaluation, complications, refractory status and prognosis. Besides epilepsy, other neurological and medical illnesses could be associated with status epilepticus. The goals of management and pharmacological approach are outlined, considering the available evidence. Prompt recognition and timely intervention, including pre-hospital treatment, are therapeutically beneficial. Refractory status should be managed in intensive care units under close monitoring. More evidence is needed for evolving the optimal treatment. A suitable treatment protocol would guide in avoiding the pitfalls at various points along the management pathway.