Anna Williams

Astrocytes—Friends or foes in multiple sclerosis?

In multiple sclerosis (MS), the presence of demyelinating plaques has concentrated researchers minds on the role of the oligodendrocyte in its pathophysiology. Recently, with the rediscovery of early and widespread loss of axons in the disease, new emphasis has been put on the role of axons and axon‐oligodendrocyte interactions in MS. Despite the fact that, in 1904, Müller claimed that MS was a disease of astrocytes, more recently, astrocytes have taken a back seat, except as the cells that form the final glial scar after all hope of demyelination is over. However, perhaps it is time for the return of the astrocyte to popularity in the pathogenesis of MS, with recent reports on the dual role of astrocytes in aiding degeneration and demyelination, by promoting inflammation, damage of oligodendrocytes and axons, and glial scarring, but also in creating a permissive environment for remyelination by their action on oligodendrocyte precursor migration, oligodendrocyte proliferation, and differentiation. We review these findings to try to provide a cogent view of astrocytes in the pathology of MS.

Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4′-methylaminophenyl)- 6-hydroxybenzothiazole

Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine‐T derivative 2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker.

Periaxin mutations cause a broad spectrum of demyelinating neuropathies

Previous studies have demonstrated that apparent loss‐of‐function mutations in the periaxin gene cause autosomal recessive Dejerine‐Sottas neuropathy or severe demyelinating Charcot‐Marie‐Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot‐Marie‐Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine‐Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate‐like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein.

Promoting repair in multiple sclerosis: problems and prospects.

Purpose of reviewDespite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy. Recent findingsSeveral hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels. SummaryDespite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.

The function of the Periaxin gene during nerve repair in a model of CMT4F

Mutations in the Periaxin (PRX) gene are known to cause autosomal recessive demyelinating Charcot‐Marie‐Tooth (CMT4F) and Dejerine‐Sottas disease. The pathogenesis of these diseases is not fully understood. However, progress is being made by studying both the periaxin‐null mouse, a mouse model of the disease, and the protein–protein interactions of periaxin. L‐periaxin is a constituent of the dystroglycan–dystrophin‐related protein‐2 complex linking the Schwann cell cytoskeleton to the extracellular matrix. Although periaxin‐null mice myelinate normally, they develop a demyelinating peripheral neuropathy later in life. This suggests that periaxin is required for the stable maintenance of a normal myelin sheath. We carried out sciatic nerve crushes in 6‐week‐old periaxin‐null mice, and, 6 weeks later, found that although the number of myelinated axons had returned to normal, the axon diameters remained smaller than in the contralateral uncrushed nerve. Not only do periaxin‐null mice have more hypermyelinated axons than their wild‐type counterparts but they also recapitulate this hypermyelination during regeneration. Therefore, periaxin‐null mice can undergo peripheral nerve remyelination, but the regulation of peripheral myelin thickness is disrupted.

A difficult case of postpartum collapse

A 29-year-old woman was brought to hospital on 24 December, having gone into labour with her third child at 34 weeks gestation. Her first two pregnancies had been uneventful and she had enjoyed an uncomplicated third pregnancy, continuing to work a farm with her husband. Past medical history included an uncorrected Ebstein’s anomaly (a congenital heart defect where the opening of the tricuspid valve is displaced towards the apex of the right ventricle due to abnormal valve leaflet formation) and spinal stabilisation for childhood scoliosis.nnAt 6.21am, she delivered a healthy baby girl by normal vaginal delivery. At 8.00am, she walked to the shower. While there, she developed a “thumping headache” and “twitching” of her left hand. She had no further recollection of events, but was found collapsed in the shower at 8.40am. When the resuscitation team arrived, her Glasgow Coma Score (GCS) was 9 (E2V2M5). She was breathing spontaneously, haemodynamically stable, but too drowsy to maintain her own airway. She was localising to pain with her right arm, but appeared not to be moving her left side. Plantar response was extensor on the left. Pupils were equal and reactive. She had a CT brain scan at 9.53am.nn#### Question 1nnWhat are the possible diagnoses?nnThis woman has most likely had a stroke. There is probably an increased risk of stroke during pregnancy and for approximately six weeks after delivery; the risk in developed countries varies between 11 and 26 per 100u2009000 deliveries.1 Studies have repeatedly identified the immediate postpartum period as the greatest period of risk. Most of these are ischaemic strokes, in part perhaps because pregnancy and the puerperium are pro-thrombotic states.nnSome ischaemic strokes in pregnancy can be attributed to specific causes such as pre-eclampsia or eclampsia, arterial dissection, antiphospholipid syndrome, postpartum angiopathy, …

Vanishing diplopia: a problem case

The care of the elderly physicians from another hospital asked us to take over the management of an 87-year-old man who lived alone. Other than osteoarthritis mainly affecting his left knee, surgery for prostatic hypertrophy four years earlier, a reducible right inguinal hernia and moderately high alcohol consumption, he had no significant medical history. He had smoked 15 cigarettes a day for many years. Remarkably, he had only used senna for occasional constipation and paracetamol for joint pain in the preceding few years. He did the Scotsman cryptic crossword daily.nnHe had attended the elderly care out-patient clinic about 10 weeks before admission complaining of poor balance and new onset of falling. He attributed the falls to tripping rather than poor balance, and had no associated loss of consciousness. Three weeks before his transfer to neurology, he had been admitted to the elderly care ward following a night-time fall. He had become tangled in his duvet and fallen to the floor where he remained, unable to get up, until morning when a neighbour found him. He had not lost consciousness or experienced other symptoms prior to or during the fall, and he could not recall hitting his head. He felt that poor balance, stiff legs, and a recent onset (3–4 weeks) of double vision caused the fall.nnOn examination at the time, his Mini-Mental State Examination score was 20 out of 30 and he had a right VI nerve palsy. The physicians thought his left leg was slightly weaker than the right, but found it difficult to be sure because of his knee pain. His reflexes were all normal and his plantar responses were flexor. The remainder of his examination was normal.nnHe had a normal full blood …