L Ginsberg

Growth hormone release in man induced by galanin, a new hypothalamic peptide

Galanin, a 29-aminoacid neuropeptide, was infused for 60 min into healthy volunteers at 7.8 pmol/kg/min (n = 4) or 33.2 pmol/kg/min (n = 6). During the infusion there was no change in heart rate or blood pressure and the only symptoms were a transitory bitter taste and slight hypersalivation. Plasma growth hormone levels rose during the high-dose galanin infusion from 2.8 +/- 0.8 mU/l to a mean peak of 48.5 +/- 19.8 mU/l; prolactin levels rose from 176 +/- 33 mU/l to 274 +/- 33 mU/l. A significant rise in growth hormone also occurred with the low-dose infusion (2.5 +/- 1.1 mU/l to a mean peak of 23.5 +/- 6.6 mU/l). There was no change in cortisol, thyroid-stimulating hormone, follicle-stimulating hormone, or luteinising hormone at either dose. 20 min after the start of the infusion a 25 g glucose bolus was given intravenously. Galanin reduced glucose clearance without significantly affecting plasma insulin concentrations. Pancreatic polypeptide levels were suppressed by the galanin infusion but levels of glucagon and gastric inhibitory peptide were unchanged.

Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain.

A significant and selective deficiency of ethanolamine plasmalogen (PPE) relative to phosphatidylethanolamine was identified in post mortem brain samples from patients with Alzheimers disease (AD). This lipid defect showed anatomic specificity, being more marked at a site of neurodegeneration in AD brain than in a region relatively spared by the disease (mid-temporal cortex vs. cerebellum) and disease specificity for AD: it was not observed at the primary site of neurodegeneration in Huntingtons disease (caudate nucleus) nor Parkinsons disease (substantia nigra). PPE deficiency parallels an inherent tendency towards membrane bilayer instability previously detected in AD brain which is necessarily due to a change in membrane lipid composition, and which may contribute to AD pathogenesis.

CNS manifestations of Fabry's disease

BACKGROUND Fabrys disease is a rare hereditary lysosomal storage disease with multiorgan involvement. Deficiency of alpha-galactosidase A activity leads to accumulation of neutral glycosphingolipids, especially in vascular endothelial and smooth-muscle cells. Along with progressive renal and cardiac dysfunction, stroke is a major and often life-threatening burden of the disease. Cerebral vasculopathy, confirmed by neuropathological, neuroradiological, and functional studies, occurs commonly and leads to ischaemic cerebrovascular events at an early age. RECENT DEVELOPMENTS Fabrys disease is an X-linked disease and women have been regarded as only mildly affected carriers. However, research has shown a high prevalence of ischaemic stroke and transient ischaemic attacks, along with imaging evidence of CNS involvement, in female patients with the disease, which suggests that at least in a subgroup of clinically affected women the severity of CNS disease is comparable to that in men. Another study has shown a high prevalence of the disease in young patients of both sexes with cryptogenic stroke, emphasising the need for more clinical attention to be paid to this under-diagnosed disease. WHERE NEXT?: These new findings should be replicated in larger samples. Brain structural changes and CNS involvement in the disease need to be monitored carefully in follow-up studies to broaden our knowledge of the course of neurobiological changes and to identify potential effects of enzyme-replacement therapy, which is already showing some benefit in cardiac and renal dysfunction in the disease. Finally, a diagnosis of Fabrys disease should always be considered in young patients who have had a stroke.

A novel RAB7 mutation associated with ulcero-mutilating neuropathy

There are two known autosomal dominant genes for the hereditary ulcero‐mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot–Marie–Tooth disease type 2B). We report a family with autosomal dominant ulcero‐mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7. Ann Neurol 2004;56:586–590

Membrane Instability, Plasmalogen Content, and Alzheimer's Disease

Abstract: The normal stability of the cell membrane bilayer depends on its lipid composition being appropriate to the ambient (physiological) temperature, Tp. Membrane lipid composition may be altered by disease such that the bilayer is only stable at a new critical temperature, T⋆, which may differ from Tp. In Alzheimers disease (AD) temporal cortex, a defect of lipid composition has previously been identified, namely, a decrease in the ratio of plasmalogen to nonplasmalogen ethanolamine glycerophospholipids. Furthermore, for AD temporal cortex neural membranes, T⋆≪ Tp, a finding confirmed in the present study in a larger series than previously, using a new method for obtaining T⋆. This inequality between T⋆ and Tp has been proposed as a putative contributory pathogenetic mechanism leading to membrane destabilisation in AD brain. The plasmalogen deficiency could account for the change in T⋆ in AD, as shown by experiments where T⋆ was measured for artificial lipid mixtures simulating brain membranes with varying plasmalogen/nonplasmalogen ratios. The critical temperature was found to be very sensitive to small alterations in plasmalogen content.

The phenotype of Charcot–Marie–Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.

Natural history of the cerebrovascular complications of Fabry disease

Fabry disease is a rare, X‐linked lysosomal storage disease caused by an inborn deficiency of α‐galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS – the Fabry Outcome Survey – and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy.

The use of nerve and muscle biopsy in the diagnosis of vasculitis: A 5 year retrospective study

Introduction: Peripheral nerve vasculitis is an important condition which can be diagnostically challenging and is one of the principal current indications for nerve and muscle biopsy. Previous studies have suggested that combined nerve and muscle biopsy (usually of the superficial peroneal nerve and peroneus brevis muscle) produces a higher diagnostic yield than nerve biopsy alone in the investigation of vasculitis. Objective: To determine whether in our two centres combined nerve (usually the sural) and muscle (usually the vastus lateralis) biopsy improved diagnostic yield compared with nerve biopsy alone. Methods: We interrogated our database of all nerve biopsies (usually of the sural nerve) performed at our institutions over 5 years and identified 53 cases of biopsy proven peripheral nerve vasculitis. Clinicopathological and neurophysiological data in these patients were reviewed. Results: The most common clinical presentation was with a painful asymmetric axonal polyneuropathy or mononeuritis multiplex (66% of cases). Nerve biopsy demonstrated definite vasculitis in 36%, probable vasculitis in 62% and no vasculitis in 2% of cases. In 24 patients a muscle biopsy (usually the vastus lateralis) was also performed and vasculitis was demonstrated in 46% of these (in 13% showing definite and 33% probable vasculitis). There was only one patient in whom vasculitis was demonstrated in muscle but not in peripheral nerve. Conclusion: Combined nerve (usually sural) and vastus lateralis muscle biopsy did not significantly increase the diagnostic yield compared with nerve biopsy alone. A sensible approach to the diagnosis of peripheral nerve vasculitis is to choose a nerve to biopsy which is clinically affected and amenable to biopsy. If the sural nerve is chosen, the data suggest that it is not routinely worth doing a vastus lateralis biopsy at the same time, whereas if the superficial peroneal nerve is chosen, it seems appropriate to do a combined superficial peroneal nerve and peroneus brevis biopsy. It is still not known if both the sural and superficial peroneal nerves are involved clinically which one gives the higher yield if biopsied.

Neurologic manifestations of the cryopyrin-associated periodic syndrome

Background: The cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable hereditary autoinflammatory condition. Without treatment, one third of patients develop amyloidosis with consequent renal failure and death. CAPS encompasses 3 conditions: familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile, neurologic, cutaneous, and articular syndrome. Neurologic complications are common in children with the chronic infantile, neurologic, cutaneous, and articular phenotype, but there are no previous published reports of neurologic features in adults with milder phenotypes. Methods: In this case series, we report in detail an adult case of CAPS and summarize the neurologic features seen in 12 other adults with genetically proven CAPS. These patients participated in a recent randomized study of canakinumab in CAPS and we used pretreatment data collected in this study. Results: Twelve of the 13 patients (92%) had headache, of whom 10 (77%) had features of migraine. Seven patients (54%) had sensorineural deafness. Nine patients (69%) reported myalgia. Six patients (46%) had papilledema and a further 2 (15%) had optic disc pallor. MRI brain scan was normal in all patients. Conclusion: CAPS is a rare but treatable condition that may be encountered by neurologists in adult clinical practice since it can present with headache, myalgia, papilledema, sensorineural deafness, and aseptic meningitis. Unrecognized and untreated, it can lead to significant morbidity and mortality from renal failure. Treatment with anti-interleukin-1 therapy leads to complete resolution of symptoms and should also prevent progression to amyloidosis and subsequent renal failure.

Difficult and recurrent meningitis.

When can the management of meningitis become difficult? Broadly speaking, there are three main potential areas of concern: View this table: Table 1 Causes of an “aseptic meningitis” cerebrospinal fluid picture* In this article, the major causes of meningitis are considered in turn, highlighting the difficulties which may arise under these three headings. Finally, the syndrome of recurrent meningitis is discussed separately, as its causes and management may differ from those of an isolated attack of acute meningitis. Inevitably, there will be overlap between the content of this article and others in the present issue, but, whenever possible, the discussion here will be restricted to immunocompetent patients. Apart from the general difficulties of establishing a clinical diagnosis of pyogenic meningitis in certain patient groups, as listed previously, specific problems may arise in the case of meningococcal infection. Thus, in a recent publication from one of the medical defence organisations,1 there …