Systematic review of current randomised control trials in chronic subdural haematoma and proposal for an international collaborative approach.

BACKGROUND: Chronic subdural haematoma (CSDH) is a pathology that is frequently encountered by neurosurgeons. Nevertheless, there is a lack of guidelines based on solid evidence. There has been a recent and considerable increase in the interest on management and outcomes for CSDH. Therefore, we systematically reviewed all currently running randomised controlled trials (RCTs) in chronic subdural haematoma to understand the areas under investigation and plan future collaborative trials. METHODS: Clinical trials databases (Cochrane Controlled Register of Trials, WHO ICTRP and clinical trials.gov) were searched for trials relevant to chronic subdural haematoma. It was then established which trials were currently running and fulfilled robust research methodology for a RCT. RESULTS: There are 26 currently running RCTs in CSDH, with the most common topics covering application of steroids (7), surgical techniques (5) and tranexamic acid (5). Further to this, there are trials running on other pharmacological agents (4), middle meningeal artery (MMA) embolisation (2) and peri-operative management (3). CONCLUSIONS: Pharmacological agents are a particular focus of CSDH management currently, and a wealth of studies on steroids will hopefully lead to more harmonised, evidence-based practice regarding this in the near future. Surgical techniques and new procedures such as MMA embolisation are also important focuses for improving patient outcomes. There is an on-going need for future RCTs and evidence-based guidelines in CSDH, particularly including low- and middle-income countries, and it is hoped that the establishment of the iCORIC (International COllaborative Research Initiative on Chronic Subdural Haematoma) will help address this.

Reversible CSF cyst related to a functioning ventriculo-peritoneal shunt.

Although the occurrence of CSF oedema and cyst has been described in presence of a blocked ventriculoperitoneal shunt, especially distal end block, its occurrence in presence of a well functioning shunt has not been described so far. We report a case where a 51-year old lady developed an insidious onset and gradually progressive CSF cyst without any clinical or radiological feature of shunt block over a period of about 2 years. The changes started about 6 months after a course of radiation therapy for an extensive residual supra and infratentorial meningioma. Following surgery, where the cyst was punctured and a new ventricular catheter was inserted, despite well functioning upper and lower end, the cyst gradually disappeared. We review the literature and hypothesize that the radiation-induced changes were responsible for initiation and progression of the cyst.

Axonal elongation through long acellular nerve segments depends on recruitment of phagocytic cells from the near-nerve environment. Electrophysiological and morphological studies in the cat.

The distal nerve stump plays a central role in the regeneration of peripheral nerve but the relative importance of cellular and humoral factors is not clear. We have studied this question by freezing the tibial nerve distal to a crush lesion in cat. The importance of constituents from the near-nerve environment was assessed by modification of the contact between the tibial nerve and the environment. Silicone cuffs, containing electrodes for electrophysiological assessment of nerve regeneration, were placed around the tibial nerve distal to the crush site. The interaction between long acellular frozen nerve segments (ANS) and the near-nerve environment was ascertained by breaching the silicone cuff to allow access of cellular or humoral components. Tibial nerves were crushed and frozen for 40 mm and enclosed in nerve cuffs with 0.45-microm holes or 2.0-mm holes to allow access of humoral factors or tissue ingrowth, respectively. In a second set of experiments, tibial nerves were crushed and either frozen for 20+20 mm, leaving a 10 mm segment with viable cells in the center (stepping-stone segment) or frozen for 50 mm. These nerves were enclosed in cuffs with 2.0 mm holes corresponding to the viable nerve segment. The regeneration was monitored electrophysiologically by implanted electrodes and after 2 months the nerves were investigated by light and electron microscopy. The results indicate that soluble substances in the near-nerve environment, such as nutrients, oxygen or tropic substances did not exert any independent beneficial effect on the outgrowing axons. However, phagocytic cells entering the acellular segment from the near-nerve environment were crucial for axonal outgrowth in long ANS.

Post reinnervation maturation of myelinated nerve fibers in the cat tibial nerve: chronic electrophysiological and morphometric studies.

The extent to which the long-term recovery of nerve fibers differs according to the cause of Wallerian degeneration is not clear, although outgrowth of axons is better after lesions with continuity of basal lamina of the Schwann cell tubes (nerve crush) compared with lesions with interruption of basal lamina (nerve section). Post-reinnervation maturation of myelinated nerve fibers of the cat tibial nerve was followed in chronic electrophysiologic studies after crushing, sectioning, and section+freeze lesions, and compared with morphometric analysis of the same nerves. The amplitudes of the compound nerve action potentials (CNAPs) recovered to a much lesser extent after sectioning than after crushing the nerve. This difference could be related to a smaller number of large fibers, a greater degree of sprouting after sectioning than after crushing, or less synchronization of conduction in regenerated fibers. In comparison, the compound muscle action potentials (CMAPs) recovered to a greater extent than the CNAP after sectioning and section+freeze, though not to the same degree or as fast as after crushing. The difference between the recovery of the CNAP and the CMAP could be due to better regeneration of motor fibers, to differences in the size of motor units or to a better summation of motor unit action potentials. The maximal conduction velocities (CV) in mixed nerve and in motor fibers increased faster after crushing than after sectioning and section+freeze to 60%-70% of control values. The diameters of the largest myelinated fibers increased in all lesions to about 80% of controls. The relation between fiber diameter and CV was influenced by remodeling of myelin during maturation. Hence, long-term functional recovery is influenced by the nature of the nerve lesion, and a smaller proportion of fibers recovered functionally after nerve section than after crush.

Axonal elongation through acellular nerve segments of the cat tibial nerve: importance of the near-nerve environment.

Peripheral nerve regeneration is considered to be influenced by structural, cellular and humoral factors in the distal nerve stump. Axonal elongation was, however, not affected by the presence of a 20 mm acellular nerve segment (ANS) distal to a crush lesion in a cat tibial nerve which was shielded from the environment by a silicone cuff [K. Fugleholm, H. Schmalbruch, C. Krarup, Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat, J. Neurosci., 14 (1994) 2659-2673]. In the present study axons were challenged to regenerate through crush lesions combined with 30-, 40-, 50-, 60- and 70-mm ANSs. For 30- and 40-mm ANSs, the nerves were shielded by impermeable silicone cuffs containing electrodes for electrophysiological evaluation of axonal elongation. All nerves were examined histologically by light microscopy 9 weeks after the lesion. The elongation through the shielded 30-mm ANS was slower than through a shielded nerve segment with viable cells. In the isolated 40-mm ANS, incomplete Wallerian degeneration and lack of blood vessels were observed, and axonal elongation was severely impaired. Regeneration across 40-70 mm non-shielded ANSs was intact and there was no relation between the number of regenerated fibers and the length of the ANS. There was no reduction in the number of blood vessels in the non-isolated ANSs. The results suggest that regeneration through an isolated acellular nerve segment exceeding 30 mm depends on cellular and humoral support from the near-nerve environment. Thus, the near-nerve environment is crucial for regeneration through long ANSs, and the importance of humoral, cellular and vascular support is discussed.

Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat.

Regeneration of axons after Wallerian degeneration is influenced by various factors localized to the distal nerve stump. We have examined elongation of axons to assess the relative influence of basal lamina and of Schwann cells in lesions with and without interruption of the Schwann cell tubes. In particular, we wanted to follow the growth of axons throughout the same distal nerve stump. Silicone cuff and patch electrodes with multiple contacts were therefore implanted around hindlimb nerves proximal and distal to the lesion. The tibial nerve was cut and sutured (15 nerves) or crushed (10 nerves). A 20-25-mm-long segment distal to the lesion was in addition frozen in four crushed and in seven sectioned nerves to eliminate the Schwann cells. Six unlesioned tibial nerves from four cats served as control. Reinnervation of plantar muscle occurred 42-54 d after nerve crushing and 42-84 d after nerve sectioning (P < 0.01). Regeneration was followed by weekly electrophysiological observations that allowed serial identification of the fastest-growing individual axons, with conduction velocities of 0.5-3 m/sec and amplitudes of 0.15-0.5 microV. Unmyelinated axons were present at the most distal lead of the electrode array from which action potentials were identified. The rate of elongation after both crushing and crush+freeze was 3-4 mm/d, and after sectioning only 2.5 mm/d (P < 0.01). Freezing in addition to sectioning was associated with even slower elongation of 1.2 mm/d. Distal to the frozen portion of the nerve elongation accelerated. Our findings suggest that regeneration was slowed throughout the nerve distal to a sectioning compared with a crushing lesion, and that depletion of Schwann cells only influenced axonal elongation after interruption of the basal lamina. This suggests that the basal lamina tubes at the lesion site may facilitate the action of neurotropic factors of distal origin.

Examination of distal involvement in cisplatin-induced neuropathy in man. An electrophysiological and histological study with particular reference to touch receptor function.

Cisplatin is a widely used anti-neoplastic agent with dose-dependent sensory neuropathy as a major side-effect. The mechanism for the neuropathy is poorly understood; it may be caused by a lesion of the dorsal root ganglion cells or by a distal axonopathy. This distinction is important since regeneration in a neuronopathy is impossible, whereas recovery may occur if the axon is affected only distally. The most distal part of the sensory nerve fibre is, however, not accessible for conventional electrophysiological examination. To ascertain whether the distal receptor-associated part of the fibre is involved, we have used a method previously untested in patients with neuropathy. In 26 males treated with cisplatin for testicular cancer 3-6.5 years previously, and in 22 normal males, the compound sensory action potentials evoked by a tactile probe were recorded through needle electrodes placed close to the sural and median nerves. The responses were compared with action potentials evoked by electrical stimulation of the same nerves. Biopsies from the distal sural nerve at the dorsolateral aspect of the foot were obtained in three patients and in four subjects not treated with cisplatin. Sixteen patients had received a conventional dose (307-435 mg/m2) of cisplatin and 10 patients had received a high dose (553-1197 mg/m2). Two-thirds of the conventional dose patients and all the high dose patients had mild to severe sensory loss and reduced or absent tendon reflexes. The amplitude of the electrically evoked sensory action potential decreased with increasing dose of cisplatin and was correlated with the reduction of vibration sense. Tactile responses, probably originating mainly from Pacinian corpuscles, were, with the exception of two high dose patients, recorded from all sural and median nerves. The two high dose patients without a tactile response had a severely reduced or no electrically evoked response at the sural nerve. The sural nerve biopsies from high dose patients showed loss of large fibres; Pacinian corpuscles were obtained in two of these patients and contained normal axons. Our findings do not suggest that cisplatin causes a primarily distal lesion with sparing of more proximal parts of the peripheral nerve. We interpret the results as being consistent with a neuronopathy affecting primarily large sensory neurons. Brainstem and somatosensory evoked potentials and H-reflexes suggested that the spinal cord and brainstem were affected as well.

Topography of unmyelinated axons in regenerated soleus nerves of the rat.

The topography of unmyelinated axons on cross sections of normal and regenerated soleus nerves of rat was studied by electron microscopy. The experimental nerves were crushed and assessed after 1-19 weeks. Unmyelinated axons in normal nerves were arranged in few groups. Nerve crush did not alter the arrangement of unmyelinated axons in the proximal nerve. Distal to the crush lesion, however, the unmyelinated axons became scattered throughout the entire cross section. The grouping of unmyelinated axons within the cross section was quantitated by means of a "clustering factor", defined as the percentage of unmyelinated axons in those 10% of the cross-sectional area which had the highest density of unmyelinated axons. The results indicate that unmyelinated axons during regeneration do not follow their original pathways.

The vascular anatomy of the cavernous body of green monkeys.

The cavernous body of monkeys was studied by light and electron microscopy. The intima of the deep artery contained longitudinal muscle cells, but cushions or valve-like structures were not found. Some branches of the deep artery directly connected to subtunical veins. Only the helicine arteries which drained into the cavernous sinuses displayed subendothelial cushions. The "epitheloid cells" forming the cushions unequivocally were smooth muscle cells. It is suggested that the helicine arteries open during tumescence, thereby diverting blood from the shunt vessels into the dilating sinuses, and that the rising intracavernosal pressure eventually occludes the shunt vessels. The endothelium of the sinuses contained many intermediate filaments, but there was no morphological evidence for the hypothesis that the cells are contractile.

Axonal branching following crush lesions of peripheral nerves of rat.

Branching of myelinated and unmyelinated nerve fibers in normal and regenerating personal and soleus nerves was studied by light and electron microscopy. There were at most 2% more myelinated and 13% more unmyelinated axons in the distal as compared with the proximal nerve segments. Two to four weeks after a crush lesion the distal axons became 2-3 times more numerous; thereafter their number decreased. The number of axons in the proximal nerve segment did not change. The number of myelinated sprouts in most regenerated nerves equalled the number of myelinated fibers in the proximal nerve, while the number of unmyelinated axons after 12-19 weeks was 18-60% higher than normal. Branching was not restricted to the crush region. The results indicate that following a crush lesion all axons branch but only branches of unmyelinated fibers persist for a prolonged period of time. It is tentatively suggested that regenerating axons branch when searching for a target and that when contact is made with the target this prevents additional branching and eliminates redundant branches. Myelinated axons are guided by existing Schwann cells, whereas unmyelinated axons do not follow predetermined pathways; this may explain their greater tendency to form permanent branches.