Assessment of patients with hereditary transthyretin amyloidosis - understanding the impact of management and disease progression.

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.

OBJECTIVE: To evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1). METHODS: In this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18-70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events. RESULTS: Between August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine. CONCLUSION: High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression. CLINICALTRIALSGOV IDENTIFIER: NCT01733407. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Anesthetic Management of Patients with Congenital Insensitivity to Pain with Anhidrosis: A Retrospective Analysis of 358 Procedures Performed Under General Anesthesia.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, absent reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The anesthetic management of patients with CIPA is challenging. Autonomic nervous system abnormalities are common, and patients are at increased risk for perioperative complications. METHODS: In this study, we describe our experience with 35 patients with CIPA who underwent 358 procedures requiring general anesthesia between 1990 and 2013. RESULTS: During surgery, 3 patients developed hyperthermia intraoperatively (>37.5°C) without prior fever. There were no cases of intraoperative hyperpyrexia (>40°C). Aspiration was suspected in 2 patients, and in another patient aspiration was prevented by the use of endotracheal tube, early detection of regurgitation, and aggressive suctioning. One patient had cardiac arrest requiring cardiopulmonary resuscitation. Intraoperative bradycardia was observed in 10 cases, and postoperative bradycardia was observed in 11 cases. CONCLUSIONS: Regurgitation, hyperthermia, and aspiration were uncommon, but the incidence of bradycardia was higher than has been reported in previous studies. CIPA remains a challenge for anesthesiologists. Because of the rare nature of this disorder, the risk of various complications is difficult to predict.

Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?

BACKGROUND: The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine-palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L-alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathy HSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy. OBJECTIVE: In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels. METHODS: Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS: Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P < .001) but had no effect on the typical sphingolipids. In contrast, extended-release niacin had no effect on 1-deoxySL levels although both treatments lowered plasma TG levels. CONCLUSIONS: The lowering of plasma 1-deoxySL levels by fenofibrate in dyslipidemic patients might be a novel therapeutic approach in the prevention and treatment of diabetic neuropathy.

Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats.

1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1-deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P < 0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P < 0.01) and therapeutic schemes (P < 0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P < 0.05). Overall NCV showed a highly significant (P = 5.2E-12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN.

El dolor muscular referido es primariamente de origen periférico: la teoría de “barrera-presa” / No disponible

Los mecanismos que llevan a una alta incidencia del dolor muscular referido (DMR) son en gran medida desconocidos. En la actualidad, se postula que se produce la activacion de una reaccion en cadena que implica el desencadenamiento de la excitacion de neuronas aferentes y la facilitacion de las conexiones sinapticas al nivel de la medula espinal, lo cual produce el DMR distribuido mas distalmente a traves de las vias convergentes eferentes. Como resultado de los hallazgos de nuestros estudios del DMR inducido experimentalmente, se puede plantear la hipotesis de que la presion profunda sobre la zona de miofibrosis incrementara primariamente la excitabilidad nociceptiva de los nervios aferentes sensitivos desde el area de DMR hasta el sitio de la presion local en el musculo en pocos segundos, lo cual a su vez excitara secundariamente el area total dependiente de DMR. El mecanismo propuesto en este articulo para el dolor muscular referido esta ligado a la teoria de la “hiperexcitabilidad pre-local” o la “teoria de barrera-presa”. Los nervios aferentes sensitivos perifericos pueden ser atrapados en los endurecimientos musculares locales (barrera-represa), con la consecuencia de la hiperexcitacion de los nervios pre-locales entre el area distal de dolor referido y la zona local muscular de sensibilidad dolorosa a la presion. La patogenesis primaria del dolor muscular referido puede ser probablemente la sensibilizacion periferica con la modulacion central adicional y no viceversa. Sin embargo, para verificar esta hipotesis, son necesarios estudios fundamentales clinicos con el DMR inducido experimentalmente (AU)

The mechanisms leading to the frequent occurrence of referred muscle pain (RP) are largely unknown. It is currently postulated that a chain reaction is activated implicating triggering of an ever-increasing number of afferent neurons and facilitation of the synaptic connection at the level of the spinal cord, causing more distally a distributed RP via convergent efferent pathways. The human interpretation of this phenomenon can be misleading when the tested person positions, after a few seconds, his RP distally from the site of pressure to the distally located RP area. As a result of what we have found in our experimentally induced RP probes, we hypothesize that deep pressure on a myofibrosis will, in the first place, within a few seconds, increase the nociceptive excitability of the afferent sensitive nerves from the RP area to the local spot of pressure on the muscle, which in return will, in the second place, excite the whole dependent RP area. The mechanism for referred muscle pain proposed in this article is linked to the ‘‘prelocal hyper-excitability theory’’ or ‘‘barrier-dam theory’’. The afferent sensitive peripheral nerves might be entrapped in local muscle hardenings (barrier-dam) with the consequence of the hyper-excitation of pre-local nerves between the distally referred pain area and the local muscular zone of tenderness. The primary pathogenesis of referred muscle pain is likely to be a peripheral sensitization with additionally a central modulation and not vice versa. Clinical and fundamental studies with experimentally induced RP are nevertheless needed to examine the hypothesis (AU)

Bisphosphonate therapy for painless fracture: change of HSAN 1 clinical course with biphosphonate and Vitamin D therapy.

Hereditary Sensory and Autonomic Neuropathies comprise a set of 5 rare neurologic conditions, little known to radiologists as the neurologic and skin abnormalities precede the radiographic changes by months or even years. We report a Caucasian patient with a clinical history of HSAN, most consistent with subtype 1, whose progressive, destructive bone changes of the foot were not only controlled but to a degree reversed by the administration of bisphosphonates (Alendronate ) and vitamin D (Colecalciferol). The authors believe that combined bisphosphonate and vitamin D therapy is the treatment of choice for progressive bony changes in HSAN1. This therapy may be beneficial in other neuropathic osteoarthropathies and possibly osteolytic bone disorders.

The debut of a rational treatment for an inherited neuropathy?

Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating L-alanine in place of L-serine, the mutant HSAN1­associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral L-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral L-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition.

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine­enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine­enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.

Neurotrophic keratitis and congenital insensitivity to pain with anhidrosis--a case report with 10-year follow-up.

PURPOSE: To report a rare case of congenital insensitivity to pain with anhidrosis. METHODS: A 3-year-old girl presented with watering in the right eye for 3 days. Slit-lamp examination showed an epithelial defect and hypopyon in the right eye and a corneal scar with thinning and vascularization in the left eye. There was bilateral reduced corneal sensation and evidence of self-mutilated lips and fingers. RESULTS: Neurological manifestations along with ocular features confirmed the diagnosis of congenital insensitivity to pain with anhidrosis. CONCLUSIONS: Patients with congenital insensitivity to pain with anhidrosis are asymptomatic even when they develop corneal ulcer. Parents should be advised regular follow-up and prompt treatment because this is a vision-threatening corneal abnormality.

Neuropatía sensible a la presión tras un parto bajo analgesia epidural / Pressure-sensitive neuropathy after obstetric delivery with epidural analgesia

Presentamos el caso de una gestante que solicitó analgesia epidural durante el trabajo de parto, con cateterización difícil del espacio epidural (múltiples punciones) y posteriormente expulsivo muy dilatado en el tiempo en camilla obstétrica. En el postparto inmediato desarrolló un cuadro de disestesias y debilidad en miembros inferiores. El seguimiento de la paciente y el estudio clínico, neurofisiológico y genético llevaron al diagnóstico de neuropatía sensible a la presión o neuropatía tomacular. Ésta es una enfermedad hereditaria que afecta a la mielina periférica, se caracteriza por episodios recidivantes de neuropatía desmielinizante focal tras traumatismos mínimos o compresión de nervios periféricos. Está probablemente infradiagnosticada, siendo muy escasas las referencias que en la literatura la relacionan con la anestesia(AU)

We report the case of a woman who requested epidural analgesia for labor in whom catheterization of the epidural space was difficult, requiring multiple punctures; furthermore, the epidural block was followed by a long expulsion phase in the delivery room. Shortly after delivery the patient experienced paresthesia and weakness in her lower limbs. A diagnosis of pressuresensitive, or tomaculous neuropathy was based on clinical observation and neurophysiologic and genetic studies. This hereditary disease, which affects peripheral nerve myelin, involves recurrent episodes of focal demyelination when nerves are injured slightly or compressed. This condition is probably underdiagnosed, as there are very few references to it in the literature on anesthesia(AU)

Omalgia pruriginosa / Pruriginous omodynia

La notalgia parestésica es una mononeuropatía sensitiva producida por atrapamiento de los ramos dorsales de las raíces espinales de D2 a D6, debido a que estos nervios se angulan 90° al pasar por la musculatura paraespinal. Se desconoce su causa, pero se ha visto relacionada con alteraciones en la estática de la columna a ese nivel (artrosis, escoliosis). Parestesias, prurito y quemazón son los síntomas más frecuentes y, junto con el hallazgo de una placa hiperpigmentada en dicha localización, constituyen los pilares de su diagnóstico. La electroneurografía muestra signos de denervación en las raíces afectadas. Únicamente la capsaicina tópica ha demostrado eficacia en ensayos clínicos. Otras terapias descritas en la literatura son la acupuntura, el bloqueo anestésico paravertebral local, la fisioterapia y la oxcarbazepina (AU)

Notalgia paresthetica is a sensory mononeuropathy producedby the dorsal spinal nerve root branch entrapmentfrom D2 to D6 because these nerves are angles 90° when passingthrough the paraspinal musculature. Its cause is unknownbut it has been observed to be related with alterationsin the spinal cord statics at this level (arthritis, scoliosis). Paresthesias,pruritus and burning sensation are the most frequentsymptoms. Together with the finding of a hyperpigmentedplaque at that location, they are the mainstay of itsdiagnosis. The electroneurography shows signs of denervationin the affected roots. Only topical capsaicin has beenshown to be effective in clinical trials. Other therapies describedin the literature are acupunture, local paravertebralblock anesthesia, physical therapy and oxcarbazepine (AU)

The pitfalls of profoundly effective analgesic therapies.

OBJECTIVE: In essentially all areas of pain medicine, treatments with improved effectiveness are needed. Though gains have been made in recent years, suffering from acute postoperative pain, low back pain, cancer-related pain, and pain from other causes remains problematic. On the other hand, both science and industry are approaching the problem with ever more sophisticated techniques. Though not currently in our armamentarium, it seems likely that at some point we will be faced with the situation where profoundly effective broad-spectrum analgesic therapies are available to our patients. Depending on their mechanisms of action, there may be significant downsides to the use of these new medications. The objective of this report was to explore the consequences of developing profoundly effective analgesic agents. METHODS: This report reviews some of the recent advancements in our march toward developing profoundly effective analgesics and some of the pitfalls we might anticipate will be associated with these agents. Specifically, the issue of pain as an essential protective mechanism is explored. The causes and consequences of inherited neuropathies associated with pain insensitivity are reviewed. RESULTS: The ability to appreciate internal and external stimuli as painful is critical to humans. The loss of this ability has profound adverse consequences which in their extreme can be life threatening. Significant social issues might arise from the availability of profoundly effective analgesics. A structure for managing the introduction of these agents into clinical practice is suggested. DISCUSSION: By anticipating the likely clinical properties of profoundly effective analgesics we place ourselves in best position to guide their development, assure their safety, and oversee their use. The early collaboration of industry, scientists, clinicians, and regulatory authorities may be the best course.

Desflurane used in a patient with congenital insensitivity to pain with anhidrosis during septic shock.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autonomic recessive disorder characterized by congenital analgesia, absence of sweating and mental retardation. Because of these abnormalities, the anesthetic managements in patients with CIPA deserve special attention. Here we report a 22-year-old man with CIPA receiving left above-knee amputation due to severe lower extremity infection. General anesthesia was maintained with desflurane, an intervention that has never been reported, and the whole course of operation was uneventful. This is also the first reported case of CIPA in Taiwan.

Neurotrophic factors and their receptors in human sensory neuropathies.

Neurotrophic factors may play key roles in pathophysiological mechanisms of human neuropathies. Nerve growth factor (NGF) is trophic to small-diameter sensory fibers and regulates nociception. This review focuses on sensory dysfunction and the potential of neurotrophic treatments. Genetic neuropathy. Mutations of the NGF high-affinity receptor tyrosine kinase A (Trk A) have been found in congenital insensitivity to pain and anhidrosis; these are likely to be partial loss-of-function mutations, as axon-reflex vasodilatation and sweating can be elicited albeit reduced, suggesting rhNGF could restore nociception in some patients. Leprous neuropathy. Decreased NGF in leprosy skin may explain cutaneous hypoalgesia even with inflammation and rhNGF may restore sensation, as spared nerve fibers show Trk A-staining. Diabetic neuropathy. NGF is depleted in early human diabetic neuropathy skin, in correlation with dysfunction of nociceptor fibers. We proposed rhNGF prophylaxis may prevent diabetic foot ulceration. Clinical trials have been disappointed, probably related to difficulty delivering adequate doses and need for multiple trophic factors. NGF and glial cell line-derived neurotrophic factor (GDNF) are both produced by basal keratinocytes and neurotrophin (NT-3) by suprabasal keratinocytes: relative mRNA expression was significantly lower in early diabetic neuropathy skin compared to controls, for NGF (P < 0.02), BDNF (P < 0.05), NT-3 (P < 0.05), GDNF (< 0.02), but not NT4/5, Trk A or p75 neurotrophin receptor (all P > 0.05). Posttranslational modifications of mature and pro-NGF may also affect bioactivity and immunoreactivity. A 53 kD band that could correspond to a prepro-NGF-like molecule was reduced in diabetic skin. Traumatic neuropathy and pain. While NGF levels are acutely reduced in injured nerve trunks, neuropathic patients with chronic skin hyperalgesia and allodynia show marked local increases of NGF levels; here anti-NGF agents may provide analgesia. Physiological combinations of NGF, NT-3 and GDNF, to mimic a 'surrogate target organ', may provide a novel 'homeostatic' approach to prevent the development and ameliorate intractable neuropathic pain (e.g., at painful amputation stumps).