Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors.

This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

The senile hand: Age effects on intrinsic hand muscle CMAP amplitudes influence split-hand index calculations.

INTRODUCTION/AIMS: Age can affect hand muscles non-uniformly. We investigated the influence of age on the compound muscle action potential (CMAP) amplitude of the hand muscles and the derived split-hand index (SHI). METHODS: We studied 244 subjects investigated for suspected myasthenia gravis but without neuromuscular disorders. Abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) CMAPs were obtained by supramaximal stimulation at the wrist, recording with surface electrodes while checking the best recording site. We applied Tukey's HSD and Kruskal-Wallis one-way analysis of variance for comparing age groups defined by median and interquantile ranges (IQRs). Spearman's rank correlation coefficient and linear regression were used for testing age-dependence of measurements. RESULTS: Median age was 61.5 y (first IQR, 44.5; third IQR, 72.0; range 18-89). Age and neurophysiological measurements were similar between genders. APBCMAP , FDICMAP , ADMCMAP , and SHI were correlated with age (P < .001). Median and cutoff values were significantly different between age groups. APBCMAP , FDICMAP , and ADMCMAP decreased by 0.8/0.7/0.3 mV/y, respectively, and SHI decreased 0.15/y. DISCUSSION: The CMAP amplitudes of hand muscles and derived SHI were strongly age-dependent, although this effect was less in ADM. This represents a physiological phenomenon. Future studies using the SHI should consider age effects.

Cardiovascular comorbidities in amyotrophic lateral sclerosis.

BACKGROUND: The role of cardiovascular risk factors in amyotrophic lateral sclerosis (ALS) is controversial. A favourable profile has been found in ALS patients, but previous studies have not specifically considered the profile in different disease phenotypes. METHODS: Demographic data, smoking habits, lifetime exercise, and medical history including diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, stroke, and cardiac events, were analysed in ALS patients and in controls with other neurological disorders, utilising a standardized questionnaire applied by the same neurologist. In ALS patients the results were analysed according to their different phenotypes. Univariate analyses and multinomial logistic models were applied to estimate the odds ratios (ORs) and confidence intervals (CIs) for covariates, to test potential modifiers and their effects. RESULTS: 500 consecutively assessed adult ALS patients (mean age 65.6, 47% women, and 136 bulbar-onset) and 327 age and gender-matched controls were studied. Patients with spinal-onset ALS took more exercise (p = 0.012), reported less hypertension (p = 0.002) and had fewer cardiac events (p = 0.012). Multinomial regression analysis showed that men without hypertension have a higher risk of having spinal-onset ALS (p < 0.001) while female with hypertension have a higher risk of having bulbar-onset ALS (p = 0.033). CONCLUSIONS: Risk-factors in ALS can be influenced by gender and phenotype. This study suggests that men with spinal ALS are healthier, exercise more and have lower rate of hypertension, but females with bulbar-onset ALS are more prone to hypertension. The complex interplay between exercise, diet and comorbidities with ALS phenotype requires further investigation.

Intensive Care Unit-Acquired Weakness: Neuropathology.

There is extensive evidence in the literature that both peripheral nerve fibers and muscle fibers are affected in the course of intensive care unit-acquired weakness. Peripheral nerve lesion is characterized by axonal degeneration, without inflammatory changes. Muscle fiber involvement is characterized by muscle fiber atrophy and loss of thick filaments, predominantly involving type 2 fibers, but myonecrosis ("acute necrotizing myopathy of intensive care") has also been reported. Steroids can precipitate thick myofilament damage, probably to some extent also triggered by immobilization and neuromuscular junction blockade. Sepsis and a systemic inflammatory response cause muscle fiber injury because of the release of cytokines and chemokines that modulate enzymatic reactions related to proteolysis. Regarding axonal injury, hyperglycemia, hypoalbuminemia, inflammatory response, and hypoperfusion are accepted risk factors. Nerve and muscle biopsy are the best methods for detection of structural abnormalities, but these are invasive investigations; although not suitable for repeated studies, in selected cases, biopsies may have a role in diagnosis.

Interleukin-6 and amyotrophic lateral sclerosis.

BACKGROUND: IL-6 is an inflammatory cytokine that is a possible factor in progression of the disease. We have investigated venous blood levels of IL-6 in controls and ALS patients in relation to clinical staging and respiratory function. METHODS: We studied 82 patients with ALS and 43 age and gender-matched healthy control subjects. Blood was drawn at the same time of day in the mornings to avoid diurnal variation. IL-6 levels were estimated according to a fixed protocol. Clinical measures included ALSFRS-R, vital capacity, and mean bilateral phrenic nerve CMAP amplitude. A multi-regression data analysis was used in addition to conventional statistical methods. RESULTS: IL-6 levels were positively correlated with increasing age in the control group. In ALS patients mean IL-6 levels were raised but the levels were markedly variable from case to case and did not reach significance (p 0.1). In addition to age effects reduction in phrenic nerve CMAP amplitude was correlated with increased IL-6 levels (p 0.026). CONCLUSIONS: IL-6 levels were physiologically influenced by aging in controls and by respiratory dysfunction in ALS. There was marked variability in levels from case to case, which might be related to respiratory factors, which cause pulmonary inflammation.

Concentric or monopolar electrode for jitter determination in orbicularis oculi.

OBJECTIVES: To investigate if monopolar (MN) and concentric (CN) electrodes are equivalent for volitional contraction jitter estimation in orbicularis oculi (OO), and to study the effect of selecting a specific high-pass filter. METHODS: We studied neuromuscular jitter in OO on both sides in 100 consecutive patients with a clinical diagnosis of ocular myasthenia gravis (MG). We used either MN (50 patients) or CN (50 patients) electrodes in individual patients, according to a randomised protocol, with a 1kH high pass filter on one side and a 3kH filter on the other. Ten or more potential pairs were studied on each side. RESULTS: 48 patients had a definite clinical diagnosis of ocular MG, and 52 of mimicking-disorders, who were analysed as controls. In controls, jitter (MCD) showed a normal distribution independent of the electrode type or filter settings. The mean jitter value and the number of abnormal pairs (>10%) was similar in MN and CN recordings, with both 1 kHz and 3 kHz filters. Sensitivity was 73% for mean jitter and 94% for number of abnormal pairs. Specificity was 100%. CONCLUSIONS: The jitter in OO using MN or CN was similar in controls and the diagnostic sensitivity was similar using either electrode in patients with ocular MG. The use of high-pass filters of 1 or 3 kHz did not influence these results. SIGNIFICANCE: MN and CN are both suitable for determining volitional jitter in OO.

Post-traumatic amnesia and confusional state: hazards of retrospective assessment.

Retrospective assessment of post-traumatic amnesia (PTA) must take into account factors other than traumatic brain injury (TBI) which may impact on memory both at the time of injury and subsequent to the injury. These include analgesics, anaesthesia required for surgery, and the development of acute or post-traumatic stress disorder. This is relevant in clinical and medicolegal settings. Repeated assessments of the post-injury state, involving tests for continuing amnesia, risk promoting recall of events suggested by the examiner, or generating confabulations. The PTA syndrome affects the categorical autobiographical memory, and is accompanied by confusion as an essential component; this should be suspected from the initial or early Glasgow Coma Scale score (13-14/15) if not directly recorded by clinical staff. PTA by itself is only one of several indices of severity of TBI. The nature of the head injury, including observers' accounts, clinical and neuroimaging data, the possible role of other external injuries, blood loss, acute stress disorder and the potential for hypoxic brain injury, must be taken into account as well as concomitant alcohol or substance abuse, and systemic shock. A plausible mechanism for a TBI must be demonstrable, and other causes of amnesia excluded.

Sensitivity of MUP parameters in detecting change in early ALS.

OBJECTIVES: We aimed to identify the most appropriate MUP parameter to evaluate reinnervation in very early ALS. METHODS: We studied tibialis anterior (TA), initially of normal strength with normal MUP analysis parameters, in 15 patients with ALS of recent onset. They were studied at the initial diagnostic assessment, and then 3 and 6 months later. Spontaneous EMG activity was recorded. Conventional MUP analysis included mean amplitude, mean area, mean duration, mean number of phases, mean number of turns, % polyphasic potentials, mean jitter, % unstable pairs and % pairs with blocking. Non-parametric statistics were utilised in the analysis. RESULTS: Fasciculations were recorded in 72% in TA and increased jitter in 33% at study entry, but without EMG features of denervation. Mean amplitude, mean duration, mean area and the three measures of neuromuscular transmission increased significantly and linearly at each evaluation. Median duration showed the lowest variation and, together with jitter, the largest relative time effect. CONCLUSIONS: Mean duration and mean jitter are the most effective measures of early reinnervation in a very early affected muscle, in ALS. SIGNIFICANCE: Mean MUP duration is a simple and easy measure that should be useful in evaluating reinnervation, for example in a future clinical trial.

Does surgery accelerate progression of amyotrophic lateral sclerosis?

BACKGROUND: Surgery is not a recognised potential amyotrophic lateral sclerosis (ALS) risk factor that might modify the onset or course of ALS. METHODS: We studied our database of ALS patients, which includes questions concerning surgical procedures. We defined surgery as an operative procedure requiring general or regional anaesthesia, but not local anaesthesia. Patients were classified as G1-no surgery; G2-surgery performed ≥3 months before disease onset; G3-surgery <3 months before disease onset; and G4-surgery after disease onset. The ALS-FRS score was evaluated every 3 months from presentation. The maximal ALS-FRS score was ascribed to disease onset, itself defined as symptom onset. RESULTS: 657 patients with ALS were studied. In G3 there was a positive correlation between onset-region and surgery-region (p=0.032). In G4, 35 (57.6%) patients had surgery, probably due to initial misdiagnosis. The rate of functional change (%) in G4 was significantly greater in the 3-month period immediately after surgery as compared with the 3-month period before (1.46%±1.35 vs. 6.30%±8.10, p=0.005) and the following 3 months (3.30%±3.10, p=0.006). CONCLUSIONS: The site of surgery before ALS onset correlates with the region of onset of ALS. Patients with slower disease progression are at an increased risk of undergoing surgery, probably as part of initial difficulty in diagnosis. We noted accelerated disease progression during the 3-month period after surgery. Definite diagnosis is important to avoid unnecessary surgical trauma and subsequent more rapid deterioration.

Vascular endothelial growth factor and amyotrophic lateral sclerosis: the interplay with exercise and noninvasive ventilation.

INTRODUCTION: We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. METHODS: We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. RESULTS: VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75% during NIV. In G4, the mean VEGF level increased by 300% during the exercise program. VEGF levels did not change during the course of the disease. CONCLUSIONS: VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself.

Neurologic complications of craniovertebral dislocation.

Craniovertebral dislocation is uncommon, but its diagnosis is important taking into account the potential severity of the neurologic complications. A number of causes are known; the most common are Down syndrome, rheumatoid arthritis, Paget's disease, other metabolic bone diseases, and craniocervical trauma. Down's syndrome is a relatively common clinical condition but craniovertebral subluxation is only observed in a small percentage of patients. About half of all cervical spine injuries affect the atlanto-occipital region and C2 vertebra. In rheumatoid arthritis, craniocervical dislocation occurs in up to 40% of patients with severe disease. In Paget's disease, involvement of the craniovertebral region occurs in about 30% of all cases. The clinical neurologic syndrome is characterized by local pain, features of upper spinal cord and medullary compression, positive Lhermitte phenomenon, syncope associated with neck flexion, vertebral artery obstruction or dissection leading to stroke, and asymmetrical lower cranial nerve palsies. Neuroimaging is essential to confirm the clinical diagnosis and to categorize severity. The treatment of this disorder is usually surgical, but traction and external immobilization is relevant in some cases. Specific conditions may require additional treatments such as radiotherapy, antibiotics, or chemotherapy.

Amyotrophic lateral sclerosis: an update.

PURPOSE OF REVIEW: The aim is to review recent publications on amyotrophic lateral sclerosis (ALS). RECENT FINDINGS: The Awaji recommendations for electrophysiological diagnosis will permit earlier clinical trials entry. The use of ultrasound to visualize fasciculations, even in deep muscles, will contribute to earlier diagnosis, as well. Unfortunately, recent clinical trials in ALS have been disappointing, as illustrated by the negative lithium trials. New, less expensive, trial designs and the inclusion of patients early in the course of ALS are positive approaches for future trials. The search for ALS biomarkers continues and a number of encouraging reports have been published, but no features unique to ALS have yet transformed this field. The most exciting advances in ALS arise from protein studies and genetics. Recognition that the ubiquitinated cytosolic inclusions in sporadic ALS, as well as in some patients with frontotemporal dementia (FTD), contain TDP-43, and that some familial cases (and a few sporadic cases) have mutations of the TDP-43 gene has transformed previous concepts on ALS pathogenesis. Other newly recognized mutations linked to ALS, such as fused-in-sarcoma (FUS) and valosin-containing protein (VCP), have not only widened the spectrum of genes involved in ALS but also consolidated the close relation between ALS and FTD. SUMMARY: ALS research is entering a new phase that should generate new proposals regarding putative therapies, or strategies for disease treatment. A continuing difficulty, however, is early clinical diagnosis and, especially, the need for identification of a unique biomarker, sensitive to clinical change in the course of the disease.

Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia (MH) susceptibility trait, Central Core Disease (CCD) and other congenital myopathies characterized by early onset and predominant proximal weakness. We report a patient presenting at 77 years with a predominant axial myopathy associated with prominent involvement of spine extensors, confirmed on MRI and muscle biopsy, compatible with a core myopathy. RYR1 mutational analysis revealed a novel heterozygous missense mutation (c.119G>T; p.Gly40Val) affecting the RYR1 N-terminus, previously predominantly associated with MH susceptibility. This case expands the spectrum of RYR1-related phenotypes and suggests that MH-related RYR1 mutations may give rise to overt neuromuscular symptoms later in life, with clinical features not typically found in CCD due to C-terminal hotspot mutations. Late-onset congenital myopathies may be under-recognised and diagnosis requires a high degree of clinical suspicion.

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies.

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.

Sarcoid polyneuropathy responsive to intravenous immunoglobulin.

We describe a 38-year-old woman with a predominantly sensory axonal polyneuropathy in whom a nerve biopsy demonstrated sarcoid granulomas. The neuropathy did not respond to oral steroid therapy but there was a rapid and repeated response to intravenous immunoglobulin, which gradually diminished over subsequent treatments, but remained beneficial. The systemic sarcoidosis remained active.