Cardiovagal and somatic sensory nerve functions in healthy subjects.

PURPOSE: Heart rate response to deep breathing (HRDB), which depends on the integrity of cardiac vagal preganglionic neurons and efferent fibers, and the function of sural nerve fibers are both associated with an age-related decline process. The aim of this study was to determine whether the effects attributed to aging on cardiovagal and sural nerve function decline are associated. METHODS: HRDB and sural sensory nerve action potential (SNAP) amplitude, latency, and conduction velocity (SCV) were measured in one hundred healthy asymptomatic subjects (aged 14-92 years, 41 women). Multiple and simple linear regressions were used to analyze the relationships between the variables. RESULTS: There were significant linear relationships between sural SNAP amplitude and HRDB with age. There was also a significant linear relationship between sural SNAP amplitude and HRDB (correlation coefficient 0.46, p<0.0001), but the model explained only 21.5 % of the variability in HRDB. CONCLUSION: Cardiovagal function assessed by HRDB is associated with sural SNAP amplitude in healthy subjects. Age-related decline only partially explained the variability seen in the association. Other genetic and environmental factors may also play a role.

Incidence of multiple sclerosis in Chile. A hospital registry study.

OBJECTIVE: To study the incidence of MS in Chile by examining the hospitalizations across all geographical regions of the country and to examine whether there is a correlation between these rates and the latitude or ultraviolet radiation. METHODS: This is a descriptive study examining the national registry of hospitalizations because of MS (code G35 in ICD-10) from January 1, 2001, to December 31, 2006. Incidence rates were calculated by gender and geographical region and standardized to the world population estimated for 2010. RESULTS: A total of 6857 hospitalizations were analyzed. There were 935 individuals; 63.9% were women. The mean incidence rate for 2002-2006 period was 0,90 (95% CI: 0.75-1.05). The annualized incidence rates for regions from North to South were as follows: I Tarapaca 0.54 (95% CI: 0.0-1.21), II Antofagasta 0,93 (0.10-1.75), III Atacama 1.07 (0.0-2.31), IV Coquimbo 0.63 (0.01-1.24), V Valparaiso 0.83 (0.38-1.27), VI O'Higgins 0.72 (0.14-1.30), VII Maule 0.52 (0.06-0.98), VIII BIO BIO 0.81 (0.41-1.21), IX Araucanía 0.43 (0.0-0.86), X Los Lagos 0.91 (0.35-1.46), XI Aysen 0.99 (0.0-2.98), XII Magallanes 3.54 (0.57-6.51), and XIII Metropolitana 1.10 (0.84-1.36). There were no significant correlations between hospitalization rates and latitude, except for region XII. UV radiation levels showed significant differences only for region XII. CONCLUSION: There is a moderate risk of MS in Chile. The southernmost region showed significantly higher incidence rates than those in the rest of the country (a cluster zone). We did not find any correlation between incidence rates and latitude or UV radiation.

Motor neurone disease.

Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.

A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group.

To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated.

Use of TRH analogues in motorneurone disease.

TRH analogues have a longer half-life than does TRH and enhanced neuropharmacological actions. In motorneurone disease (MND), no benefit was reported with MK771 and DN1417. Focal, transient, and slight improvements in weakness and spasticity were described with CG3509. A controlled trial with a single intravenous dose of RX 77368 showed improvements in dysarthria, tongue movements, respiration, swallowing, and spasticity lasting up to 72 hours. Changes in muscle force were of no functional significance. There was an acute 25-30% increase in mean corrected fiber density and in mean macro-EMG parameters in biceps, but no change in amplitude or area of single macro-EMG motor units followed during the 2-hour infusions. An acute, direct or indirect, central effect of RX77368 on recruitment order or on activation threshold of pathological motor units is suggested. In a subacute open trial with repeated intravenous infusions of RX77368 (median 2 weeks), improvement in bulbar function in 8 of 12 responders, cramps (5 of 9), and spasticity (5 of 8) were maintained for medians of 18, 14, and 7 days, respectively. Side effects were prominent with doses above 0.2 mg/kg. Disease progression has not been halted with any analogue, but whether it may be usefully slowed down with RX77368 is worth investigating.

Accuracy, reproducibility and variability of quantitative assessments of bulbar and respiratory function in motor neurone disease.

The validity of quantitative tests to assess bulbar and respiratory function used in therapeutic trials in motor neurone disease (MND) is studied in 26 MND and 21 age- and sex-matched control subjects. Five raters timed repeated visual and auditory stimuli generated by a metronome simulating bulbar tests. For all raters, mean error rate was 5.07%, correlation coefficient was 0.89 (and %difference of 1.53), and coefficient of variation (CV) was 3.18%. The experienced rater obtained significantly better %differences and CV. For all subjects and tests, mean correlation coefficient was 0.98, and mean CV was 8.8%. There were no significant differences in reproducibility or variability in readings obtained in MND and control subjects assessed by the experienced rater. The use of composite bulbar, but not respiratory, scores resulted in significant improvements in reproducibility and variability.

Interneuronal survival and calbindin-D28k expression following motoneuron degeneration.

Degeneration of both motoneurons and interneurons has been previously observed in amyotrophic lateral sclerosis. It is unclear whether interneuronal loss is due to an intrinsic neuronal defect or if it occurs secondary to loss of their target motoneurons. We have examined the target dependence of interneurons, their survival and alterations in the expression of the calcium binding protein, calbindin-D28k (CB), in the ventral horn of the rat lumbar cord after extensive motoneuron degeneration was induced by unilateral rhizotomy of spinal nerves L2-L6 at postnatal day 3 (P3). Counts of Nissl-stained cells at P21 revealed no significant interneuronal death despite loss of 80% of their target motoneurons. At P6, some motoneurons transiently expressed CB on the operated side compared to the control side. Since most of these cells are destined to die, this transiently increased CB expression may represent an abortive attempt by the axotomised motoneurons to buffer the neurotoxic consequences of high intracellular calcium. In contrast, there was a time-dependent decrease in CB expression in ventral horn interneurons, with only 35% of putative Renshaw cells expressing CB by P21. These results indicate that neonatal interneurons are capable of surviving the loss of their motoneuron targets, but alter their phenotype as indicated by functional alterations in calcium-binding proteins.

AIDS-associated vacuolar myelopathy and tumor necrosis factor-alpha (TNF alpha).

The spinal cords from 15 patients with AIDS-associated vacuolar myelopathy (VM), 4 AIDS patients without VM, and 5 HIV-seronegative controls, were studied with immunocytochemistry for TNF alpha. CSF and blood from HIV-seropositive patients with VM (n = 16), non-vacuolar myelopathies (n = 8), CNS infection but no clinical myelopathy (n = 31), no clinical or radiological evidence of CNS disease (n = 9), and from 7 HIV-seronegative controls with motor neurone disease were assayed for TNF alpha using an ELISA technique. TNF alpha was present on immunostaining in all the 15 cords with VM studied. The stained cells were macrophages, microglia and endothelial cells. The amount of immunostaining was higher in cords with VM compared with cords from HIV-seropositive patients without VM (p = 0.001). The distribution of staining corresponded to the areas of pathology but did not correlate with the severity of the VM. Immunostaining was also higher in the HIV-seropositive group compared to the HIV-seronegative controls (p = 0.001). There was no significant difference in the levels of TNF alpha in the CSF of patients with VM compared to any of the other groups studied. Blood levels of TNF alpha were lower in the HIV-seropositive controls without CNS disease and in the HIV-seronegative MND controls, than in patients with VM, non-vacuolar myelopathies, and CNS disease. CSF TNF alpha levels did not appear to be a reliable indicator of intramedullary levels. The findings support the hypothesis that TNF alpha may be relevant in the pathogenesis of vacuolar change in VM.

Natural history of amyotrophic lateral sclerosis. Observations with the Charing Cross Amyotrophic Lateral Sclerosis Rating Scales.

Natural history data increase the descriptive knowledge about amyotrophic lateral sclerosis (ALS), help define primary outcome variables and numbers of patients needed on clinical trials, and may give valuable predictive information. Global scores do not adequately represent the clinical variability of ALS. The Charing Cross Quantitative and Qualitative ALS Rating Scales assess disease severity and progression by validated regional scores (bulbar, respiration, upper limb, lower limb) and activities of daily living. The main stages in the development of these scales are summarized. Interval, or quantitative, scales provide accurate and sensitive measurements of the evolution of the disease and are useful for phase II therapeutic trials. The deterioration rates of regional scores in individual patients may not be linear. Rates of disease progression in ALS vary (1) among patients, (2) among topographical regions within a single patient, and (3) at different stages of the disease in a single region in the same patient. The deterioration rates of the regional scores of an ALS population depend critically on whether deaths are included or excluded from the population mean scores. Qualitative scales with simple scores are best suited for large-scale, phase III trials and for life table analysis of times to failure.

Observations on the clinical assessment of patients with motor neuron disease. Experience with a TRH analogue.

The need for improved assessment techniques in order to monitor the action of substances active in upper and lower motor neuron systems in motor neuron disease is discussed. A long-acting TRH analogue is shown to have detectable acute effects on bulbar symptoms, particularly speech, tone, fasciculations, and muscle force. Endocrine surveillance is essential in studies with TRH and analogues.

Chronic basal meningitis and vasculitis in acquired immunodeficiency syndrome. A possible role for human immunodeficiency virus.

We describe the clinical and postmortem findings in a 57-year-old man with human immunodeficiency virus who presented with neurologic symptoms attributed to stroke. In addition to multiple foci of ischemic necrosis, pathologic examination of the brain showed chronic basal meningitis and vasculitis. No microorganisms were found. The association of meningitis and vasculitis in patients with acquired immunodeficiency syndrome is unusual and the possibility that these conditions may be due to primary human immunodeficiency virus infection is raised.

Morton's metatarsalgia. Clinical, electrophysiological and histological observations.

In an attempt to improve the accuracy of diagnosis, 16 patients suffering from Morton's metatarsalgia were investigated clinically and electrophysiologically. The histological findings were related to these observations. The precise aetiology of Morton's metatarsalgia remains obscure, but the findings are compatible with an entrapment syndrome. Nerve conduction studies have a place in the investigation of patients with atypical presentation of pain in the foot. Further refinement of the electrophysiological technique should be possible.

AIDS: neurological opportunist infections in central London.

Twenty six (41%) of 64 central London cases of AIDS with nervous system involvement during the course of the illness had neurological opportunist infection. Cytomegalovirus and Toxoplasma gondii were the commonest agents in 22 cases with central nervous system (CNS) infection. Eight cases had herpes zoster radiculopathy. Other infections included those caused by Cryptococcus neoformans, Mycobacterium tuberculosis and papova JC virus. Prognosis was generally poor, irrespective of whether the opportunist infection was treatable.

Neurological presentations of AIDS--when to test for HIV.

Nine of 122 patients dead from AIDS in central London presented with neurological disease, confirmed pathologically in seven. Seven had no other major systemic manifestations. AIDS needs to be considered in the differential diagnosis of meningitis, dementia, diffuse and focal encephalopathies, brainstem syndromes, myelopathy, visual failure and peripheral nerve syndromes. As AIDS becomes more widespread there will be an increasing need for diagnostic HIV testing in many neurological syndromes.

Peripheral nerve conduction in Miller Fisher syndrome.

Two cases of acute ophthalmoplegia, ataxia, and arreflexia with high CSF protein are reported (Miller Fisher syndrome). Detailed EMG and nerve conduction studies showed abnormal conduction in peripheral sensory fibres from the initial stages of the illness in both patients. Careful review up to 10 months after the onset was required to document the sensory conduction abnormality properly in one of them. The electrical findings did not differ from those that can be seen in the Guillain-Barré syndrome and provided no clues as to the mechanism of the ataxia.