Berberine enhances survival and axonal regeneration of motoneurons following spinal root avulsion and re-implantation in rats.

Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA.

Nerve root injection cancellations because of incomplete anticoagulation management.

BACKGROUND: Computed tomography-guided steroid injection is a well-recognized, conservative treatment of localized spinal pain as a result of facet arthropathy and radiculopathy secondary to nerve root compression. An extremely rare complication is the development of an epidural haematoma with potential to cause permanent neurological damage, so anticoagulation at the time of procedure is contraindicated. Routinely injections are performed as an outpatient requiring the referring physician to implement a peri-procedural anticoagulation plan. Anecdotal experience suggested that cancellations were occurring as patients remained on anticoagulation at the time of their appointment. The authors therefore assessed the existing service against expected standards to identify the causes of cancellations and find ways to improve the service. AIMS: This audit aimed to identify the incidence of cancelled computed tomography-guided nerve root injections secondary to incorrect peri-procedural anticoagulation management, develop an intervention to help reduce the incidence of cancellations and then re-audit to assess the effect of the intervention. METHODS: The audit standard was that 100% of outpatients attending for computed tomography-guided nerve root and facet injections should have an appropriate anticoagulation plan implemented. Baseline data collection took place prospectively between 1 September and 30 November 2016. The study population was elective computed tomography-guided spinal nerve root and facet injections scheduled on the radiology information system at the authors' trust. Descriptive analysis was completed. The intervention involved a revised electronic request form being implemented with new compulsory fields concerning antiplatelets and anticoagulants. Re-audit post-intervention involved prospective data collection between 1 September and 30 November 2017 using the same methods. RESULTS: Baseline audit found that of three out of 55 (5%) patients had cancellations. On re-audit, there were 0 cancellations out of 93 patients. CONCLUSIONS: The new request form prevented 5% of patients referred for computed tomography-guided nerve root injection being cancelled because of incorrect anticoagulation management. Extrapolated over the year the potential savings through preventing lost activity are £3445.56.

Magnetic resonance imaging conditionally safe neurostimulation leads: investigation of the maximum safe lead tip temperature.

BACKGROUND: Magnetic resonance imaging (MRI) is preferred for imaging the central nervous system (CNS). An important hazard for neurostimulation patients is heating at the electrode interface induced, for example, by 64-MHz radiofrequency (RF) magnetic fields of a 1.5T scanner. OBJECTIVE: We performed studies to define the thermal dose (time and temperature) that would not cause symptomatic neurological injury. METHODS: Approaches included animal studies where leads with temperature probes were implanted in the brain or spine of sheep and exposed to RF-induced temperatures of 37 °C to 49 °C for 30 minutes. Histopathological examinations were performed 7 days after recovery. We also reviewed the threshold for RF lesions in the CNS, and for CNS injury from cancer hyperthermia. Cumulative equivalent minutes at 43 °C was used to normalize the data to exposure times and temperatures expected during MRI. RESULTS: Deep brain and spinal RF heating up to 43 °C for 30 minutes produced indistinguishable effects compared with 37 °C controls. Exposures greater than 43 °C for 30 minutes produced temperature-dependent, localized thermal damage. These results are consistent with limits on hyperthermia exposure to 41.8 °C for 60 minutes in patients who have cancer and with the reversibility of low-temperature and short-duration trial heating during RF lesion procedures. CONCLUSION: A safe temperature for induced lead heating is 43 °C for 30 minutes. MRI-related RF heating above 43 °C or longer than 30 minutes may be associated with increased risk of clinically evident thermal damage to neural structures immediately surrounding implanted leads. The establishment of a thermal dose limit is a first step toward making specific neurostimulation systems conditionally safe during MRI procedures.

Chronic nerve root entrapment: compression and degeneration.

Electrode mounts are being developed to improve electrical stimulation and recording. Some are tight-fitting, or even re-shape the nervous structure they interact with, for a more selective, fascicular, access. If these are to be successfully used chronically with human nerve roots, we need to know more about the possible damage caused by the long-term entrapment and possible compression of the roots following electrode implantation. As there are, to date, no such data published, this paper presents a review of the relevant literature on alternative causes of nerve root compression, and a discussion of the degeneration mechanisms observed. A chronic compression below 40 mmHg would not compromise the functionality of the root as far as electrical stimulation and recording applications are concerned. Additionally, any temporary increase in pressure, due for example to post-operative swelling, should be limited to 20 mmHg below the patient's mean arterial pressure, with a maximum of 100 mmHg. Connective tissue growth may cause a slower, but sustained, pressure increase. Therefore, mounts large enough to accommodate the root initially without compressing it, or compliant, elastic, mounts, that may stretch to free a larger cross-sectional area in the weeks after implantation, are recommended.

Corticospinal sprouting occurs selectively following dorsal rhizotomy in the macaque monkey.

The corticospinal tract in the macaque and human forms the major descending pathway involved in volitional hand movements. Following a unilateral cervical dorsal root lesion, by which sensory input to the first three digits (D1-D3) is removed, monkeys are initially unable to perform a grasp retrieval task requiring sensory feedback. Over several months, however, they recover much of this capability. Past studies in our laboratory have identified a number of changes in the afferent circuitry that occur as function returns, but do changes to the efferent pathways also contribute to compensatory recovery? In this study we examined the role of the corticospinal tract in pathway reorganization following a unilateral cervical dorsal rhizotomy. Several months after animals received a lesion, the corticospinal pathways originating in the primary somatosensory and motor cortex were labeled, and terminal distribution patterns on the two sides of the cervical cord were compared. Tracers were injected only into the region of D1-D3 representation (identified electrophysiologically). We observed a strikingly different terminal labeling pattern post lesion for projections originating in the somatosensory versus motor cortex. The terminal territory from the somatosensory cortex was significantly smaller compared with the contralateral side (area mean = 0.30 vs. 0.55 mm2), indicating retraction or atrophy of terminals. In contrast, the terminal territory from the motor cortex did not shrink, and in three of four animals, aberrant terminal label was observed in the dorsal horn ipsilateral to the lesion, indicating sprouting. These differences suggest that cortical regions play a different role in post-injury recovery

Fluoroscopically guided transforaminal epidural dry needling for lumbar spinal stenosis using a specially designed needle.

BACKGROUND: This report describes the methodological approach and clinical application of a minimally invasive intervention to treat lumbar spinal stenosis (LSS). METHODS: Thirty-four patients with LSS underwent fluoroscopically guided transforaminal epidural dry needling using a specially designed flexed Round Needle. The needle was inserted 8-12 cm lateral to the midline at the level of the stenosis and advanced to a position between the anterior side of the facet joint and pedicle up to the outer-third of the pedicle. The needle was advanced medially and backed laterally within a few millimetres along the canal side of the inferior articular process between the facet joint and pedicle. The procedure was completed when a marked reduction in resistance was felt at the tip of the needle. The procedure was performed bilaterally at the level of the stenosis. RESULTS: The average follow-up period was 12.9 +/- 1.1 months. The visual analogue scale (VAS) pain score was reduced from 7.3 +/- 2.0 to 4.6 +/- 2.5 points, the Oswestry Disability Index (ODI) score decreased from 41.4 +/- 17.2 to 25.5 +/- 12.6% and the average self-rated improvement was 52.6 +/- 33.1%. The VAS scores indicated that 14 (41.2%) patients reported a "good" to "excellent" treatment response, while 11 (32.4%) had a "good" to "excellent" treatment response on the ODI and 22 (64.7%) had a "good" to "excellent" treatment response on the self-rated improvement scale. CONCLUSIONS: These results suggest that fluoroscopically guided transforaminal epidural dry needling is effective for managing LSS.

Evaluation of the effectiveness of lumbar interlaminar epidural injections in managing chronic pain of lumbar disc herniation or radiculitis: a randomized, double-blind, controlled trial.

BACKGROUND: The pathophysiology of lumbar radicular pain is the subject of ongoing research, with a reported prevalence of sciatica or radiculitis ranging from 1.2% to 43%. Among the numerous non-surgical interventions available, epidural injections are the most commonly performed interventions in the United States in managing chronic low back and lower extremity pain. STUDY DESIGN: A randomized, double-blind, controlled trial. SETTING: An interventional pain management practice, a specialty referral center, a private practice setting in the United States. OBJECTIVE: To evaluate the effectiveness of lumbar interlaminar epidural injections with local anesthetic, with or without steroids, in managing chronic low back and lower extremity pain secondary to disc herniation or radiculitis in providing effective and long-lasting pain relief. METHODS: Patients were assigned to one of 2 groups with local anesthetic only or with local anesthetic mixed with non-particulate betamethasone. Randomization was performed by computer-generated random allocations sequence by simple randomization. Seventy patients were included in this analysis. OUTCOMES ASSESSMENT: Patient outcomes were measured at baseline, 3, 6, and 12 months post-treatment with the Numeric Rating Scale (NRS), the Oswestry Disability Index 2.0 (ODI), employment status, and opioid intake. Decrease of > or = 50% of NRS scores and Oswestry scores were considered significant. RESULTS: Significant pain relief (> or = 50%) was seen at 12 months in 74% of patients in Group I and 86% in Group II, and 69% and 83% in ODI scores respectively. Significant differences were noted in pain relief characteristics at 6 months between Group I and Group II (p = 0.001) and functional status improvement was significantly better in Group II at 6 months and 12 months (p = 0.019 and 0.045). The overall average procedures per year were 4.3 in Group I and 4.2 in Group II with an average total relief per year of 42.2 +/- 10.5 weeks in Group I and 41.4 +/- 11.0 weeks in Group II over a period of 52 weeks in the successful group. LIMITATIONS: The study limitations include the lack of a placebo group and the fact that this is a preliminary report of 35 patients in each group. CONCLUSION: Overall, 74% of patients in Group I without steroids and 86% in Group II with steroids with lumbar disc herniation or radiculitis might benefit from lumbar interlaminar epidural injections.

Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain.

Lysophosphatidic acid receptor (LPA(1)) signaling initiates neuropathic pain through demyelination of the dorsal root (DR). Although LPA is found to cause down-regulation of myelin proteins underlying demyelination, the detailed mechanism remains to be determined. In the present study, we found that a single intrathecal injection of LPA evoked a dose- and time-dependent down-regulation of myelin-associated glycoprotein (MAG) in the DR through LPA(1) receptor. A similar event was also observed in ex vivo DR cultures. Interestingly, LPA-induced down-regulation of MAG was significantly inhibited by calpain inhibitors (calpain inhibitor X, E-64 and E-64d) and LPA markedly induced calpain activation in the DR. The pre-treatment with calpain inhibitors attenuated LPA-induced neuropathic pain behaviors such as hyperalgesia and allodynia. Moreover, we found that sciatic nerve injury activates calpain activity in the DR in a LPA(1) receptor-dependent manner. The E-64d treatments significantly blocked nerve injury-induced MAG down-regulation and neuropathic pain. However, there was no significant calpain activation in the DR by complete Freund's adjuvant treatment, and E-64d failed to show anti-hyperalgesic effects in this inflammation model. The present study provides strong evidence that LPA-induced calpain activation plays a crucial role in the manifestation of neuropathic pain through MAG down-regulation in the DR.

Intracranial hypotension syndrome following chiropractic manipulation of the cervical spine.

Cervical spine manipulation has been associated with several disorders such as cervical arteries dissection, but rarely has a relationship with intracranial hypotension been reported. We describe a patient showing intracranial hypotension syndrome following chiropractic cervical spine treatment. Magnetic resonance showed the presence of dural leakage at cervical level, suggesting the pathogenesis of the syndrome. We state that cervical spine manipulation should be considered a treatment with risk of neurological complications, including the occurrence of intracranial hypotension.

Detection of root avulsion in the dominant C7 obstetric brachial plexus lesion: experience with three-dimensional constructive interference in steady-state magnetic resonance imaging and electrophysiology.

OBJECTIVE: Preoperative, reliable detection by ancillary investigations of spinal nerve root avulsions in infants with severe obstetric brachial plexus lesions to avoid ineffective operative repair from deceivingly intact but actually avulsed nerve roots. METHODS: Ten infants were selected with an infrequent, severe dominant C7 lesion, primarily because of the anatomically distinct supraclavicular course of this spinal nerve. Three-dimensional constructive interference in steady-state magnetic resonance imaging (3D CISS MRI) studies under mild sedation were performed and evaluated for detection of avulsed nerve roots by two experienced neuroradiologists. Preoperative electrodiagnostics (electromyography and somatosensory evoked potentials) as well as intraoperative somatosensory potentials and muscle contractions after electrostimulation were recorded. Preoperative and intraoperative ancillary investigations were correlated with intraoperative findings in eight patients and clinical status in two children who recovered spontaneously. RESULTS: Despite two minor motion artifacts, the quality of the 3D CISS MRI studies was good. In 8 of 10 patients, prediction of root continuity was consistent with operative or clinical findings, and 2 remained doubtful. Preoperative and intraoperative electrodiagnostics tended not to correlate with intraoperative findings in this small, selected group. CONCLUSION: 3D CISS MRI provides good images of anterior and posterior spinal roots in infants with obstetric brachial plexus lesions. Images seem to allow accurate prediction of root avulsion in the majority of patients. In this study, electrodiagnostics were of limited value.

[Non-cerebrovascular complication in chirotherapy manipulation of the cervical vertebrae]. / Nicht-zerebrovaskuläre Komplikationen der chirotherapeutischen HWS-Manipulation.

PURPOSE: Chirotherapy is a popular and successful management option for reversible functional disorders of the cervical spine. Though rarely observed, complications do occur, mainly involving the cerebrovascular system. By means of the here described case and a literature survey, we aim to highlight non-cerebrovascular complications of chirotherapeutic cervical spine manipulation. RESULTS: A 43-year-old male initially consulted an ENT specialist, suffering from tinnitus aurium and loss of hearing ability. His hearing significantly increased after intravenous drug therapy, but the tinnitus remained. During chiropractic manipulation of the cervical spine by an orthopaedic surgeon for the tinnitus, the patient described severe neck pain following a clearly audible clicking sound. Scans of the cervical spine prior to and after manipulation showed an intracapsular/intraosseus oedema of the facet joints C2/C3 with lesion of the nerve root C3, most probably induced by chirotherapy. CONCLUSION: Although complications after chiropractic manipulation are extremely rare, treatment of the spine, especially the cervical spine, is not wholly harmless. An adequate history taking followed by clinical and radiographic patient evaluation is necessary to keep the risk of iatrogenic trauma at a minimum. Above all, the chiropractic manipulation of the cervical spine belongs in the hands of a qualified and experienced medical practitioner.

NT-3 attenuates functional and structural disorders in sensory nerves of galactose-fed rats.

The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections. After 2 months, sciatic and saphenous sensory nerve conduction velocity (SNCV) and sciatic motor nerve conduction velocity (MNCV) were measured and the sciatic, sural, peroneal and saphenous nerves and dorsal and ventral roots processed for light microscopy. Treatment of control animals with NT-3 had no effect on any functional or structural parameter. Compared to control values, galactose feeding induced a sensory and motor nerve conduction deficit and a reduction in axonal caliber. Treatment with 5 and 20 mg/kg NT-3 ameliorated deficits in sciatic and saphenous SNCV in galactose-fed rats but had no effect on the MNCV deficit. NT-3 treatment also attenuated the decrease in mean axonal caliber in the dorsal root and sural nerve but not in the saphenous nerve, ventral root and peroneal nerve. These observations show that NT-3 can selectively attenuate the sensory conduction deficit of galactose neuropathy in a dose-dependent manner that depends only in part on restoration of axonal caliber of large-fiber sensory neurons.

Origin of short-latency somatosensory evoked potentials to median nerve stimulation in the cat. Comparison of the recording montages and effect of laminectomy.

Short-latency somatosensory evoked potentials were recorded from 23 cats with the frontal-neck, scalp-ear and scalp-noncephalic reference montages. In the frontal-neck recordings, four or five components (n9, n11, n13a, n13b and n14) were identified, whereas three components (p15, p18 and p20) were recorded in the scalp-ear leads. The noncephalic reference recordings had four to six components (p9, p10, p11, p13a, p13b and p14). The origin of these components was investigated by recording direct from the attributed generators and examining the effects of lesions. The suggested generators are as follows: n9, p9 and p10-peripheral nerve; n11, p11-dorsal column; n13a-segmental dorsal horn; p13a-spinocerebellar tract; n13b and p13b-cuneate nucleus and caudal part of the medial lemniscus; n14, p14 and p15-rostral part of the medial lemniscus; p18-thalamocortical radiation; p20-primary somatosensory cortex. Components with similar latencies such as n13a and p13a in the frontal-neck and noncephalic reference recordings had different generators. In the noncephalic reference recordings, the axially orientated dipoles, including the potential produced by the spinocerebellar tract (p13a) were clearly detectable, but the transversely orientated dipole of the segmental dorsal horn (n13a) was indistinct. The frontal-neck montage was distorted by the frontal 'reference' electrode active for part of the axially ascending volleys (p13a in some cats and p14), but could pick up the near-field potentials in the segmental dorsal horn (n13a). Desynchronized volleys in fibre tracts such as the spinothalamic tract did not contribute significantly to the potentials recorded from the skin, whereas the synaptic potential in the cuneate nucleus was shown to have a steep onset and open-field distribution with its dipole orientated in part axially, and was recorded in the noncephalic reference montage. The p9 and p11 positivities fused after laminectomy, suggesting that conductance change at the root entry to the bony spinal canal separates these components in the noncephalic reference recording.

Axonal dystrophy in a case of connatal thalamic and brain stem degeneration.

A neonate with a rapidly fatal disease characterized by connatal hypertonia and arthrogryposis multiplex is described. Neuropathological investigations revealed bilateral thalamus and brain stem degeneration, axonal degeneration of pyramidal and other tracts in the spinal cord, and axonal spheroids in areas of origin of lower motor neurons and in the brain stem reticular substance. Congenital thalamic and brain stem degeneration is generally assumed to be the result of intrauterine asphyxia. The widespread occurrence of axonal spheroids in the present neonate points to the possibility of a genetic or toxic origin for at least some of these cases.

The effect of suppression of macrophage activity on the development of experimental allergic neuritis.

The selective toxicity of silica dust for macrophages has been used to assess the role of these cells in experimental allergic neuritis (EAN). Inbred Lewis rats were inoculated with bovine dorsal roots in Freund's complete adjuvant (day 0). In two experiments, animals received 200 mg of silica dust in 1 cm3 of saline intraperitoneally (IP) at days 8 and 16. In another two experiments, animals received IP silica at days 3, 7, and 11. Control animals received 1 cm3 saline IP at corresponding times. Regular clinical assessment showed that in animals treated on days 8 and 16 there was a significant delay in the time taken to reach their maximum degree of illness. This delay was not seen in the animals treated on days 3, 7, and 11. Neither of the injection regimes reduced the final maximum severity of the disease. In three experiments recovery of the treated and control animals occurred concurrently, hence the duration of the disease was reduced in the animals treated at days 8 and 16. However, in one group of animals given silica at days 3, 7 and 11, there was a delay in the time taken to recover from the most severe phase of the disease but thereafter the treated animals improved more quickly to reach their best grade at the same time as the controls. If the silica blockade of macrophages is to be effective in delaying the onset of EAN, the timing of injections is critical.

A neuropathologic study of Werdnig-Hoffmann disease with special reference to the thalamus and posterior roots.

The brains of five cases of severe infantile form of Werdnig-Hoffmann (W-H) disease were studied to observe the pathologic changes of sensory neurons and the thalamus. The present study disclosed severe cell loss, chromatolytic degeneration, and empty cell beds of the spinal anterior horn and cranial motoneurons (V, VII, X, XII). Glial bundles were also noted in the anterior roots. In the sensory systems, glial bundles in the posterior roots (2/5), ghost cells in Clarke's column (2/5), and degeneration of the thalamus, mainly in the lateral formation (4/4) were noted. It was demonstrated that not only degeneration of lower motor neurons and glial bundles in the anterior roots, but also degeneration of sensory neurons and thalamus were present in W-H disease. These findings suggested the possibility that W-H disease is a multisystemic disease involving both the anterior and posterior root systems. No sensory involvement was found clinically. Characteristic wrist drop was observed in four cases, two of which also having motor nerve conduction velocity (MCV) delay. On the other hand, MCV of another case without wrist drop was normal. The possibility that wrist drop might be one of the clinical features of peripheral nerve dysfunction was discussed, but further pathologic evaluation of peripheral nerves is needed.