Autonomic neuropathies

Autonomic neuropathies represent a complex group of disorders that preferentially target autonomic fibers and can be classified as either acute/subacute or chronic in onset. Acute‐onset autonomic neuropathies manifest with such conditions as paraneoplastic syndromes, Guillain‐Barre syndrome, Sjögren syndrome, infection, or toxins/chemotherapy. When the presentation is acute, immune‐mediated, and without a secondary cause, autoimmune autonomic ganglionopathy is likely, and should be considered for immunotherapy. Of the chronic‐onset forms, diabetes is the most widespread and disabling, with autonomic impairment portending increased mortality and cardiac wall remodeling risk. Acquired light chain (AL) and transthyretin (TTR) amyloidosis represent two other key etiologies, with TTR amyloidosis now amenable to newly‐approved gene‐modifying therapies. The COMPASS‐31 questionnaire is a validated outcome measure that can be used to monitor autonomic severity and track treatment response. Symptomatic treatments targeting orthostatic hypotension, among other symptoms, should be individualized and complement disease‐modifying therapy, when possible.     

Autonomic involvement in inherited neuropathies

The inherited peripheral neuropathies constitute a large group of disorders, in some of which the causative metabolic defect has been identified whereas in the majority it is still unknown. Amongst the former, autonomic involvement is an important component in porphyric neuropathy, in the familial amyloid polyneuropathies, in Fabry's disease and in dopamine-hydroxylase deficiency. The latter group includes the hereditary sensory and autonomic neuropathies in some of which, such as the Riley-Day syndrome, autonomic disturbances are prominent, whereas in others they constitute only a minor component of the symptomatology. Autonomic dysfunction is an important component of the neurological manifestations in multiple endocrine neoplasia type IIB.     

Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (also called diabetic amyotrophy) is a well-recognized subacute, painful, asymmetric lower-limb neuropathy that is associated with weight loss and type II diabetes mellitus. Nondiabetic lumbosacral radiculoplexus neuropathy (LRPN) has received less attention. Comparison of large cohorts with DLRPN and LRPN demonstrated that age at onset, course, type and distribution of symptoms and impairments, laboratory findings, and outcomes are similar. Both conditions are lumbosacral radiculoplexus neuropathies that are associated with weight loss and begin focally with pain but that evolve into widespread, bilateral paralytic disorders. Although both are monophasic illnesses, patients have prolonged morbidity from pain and weakness, and many patients become wheelchair-dependent. Although motor-predominant, there is unequivocal evidence that autonomic and sensory nerves are also involved. Cutaneous nerves from patients with DLRPN and LRPN show pathological evidence of ischemic injury (multifocal fiber loss, perineurial thickening and degeneration, neovascularization, microfasciculation, and swollen axons with accumulated organelles) and microvasculitis (mural and perivascular inflammation, separation and fragmentation of mural smooth muscle layers of microvessels and hemosiderin-laden macrophages). Controlled trials with immune-modulating therapies in DLRPN are in progress, and preliminary data suggest that such therapy may be beneficial in LRPN. It is likely that DLRPN and LRPN are immune-mediated neuropathies that should be separated from chronic inflammatory demyelinating polyneuropathy and from systemic necrotizing vasculitis.     

Immune mediated neuropathies

Abstract. This paper reviews recent treatment strategies of immune mediated neuropathies, in particular it includes data regarding Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), neuropathy with IgM monoclonal gammopathy and other dysglobulinemic neuropathies. In the treatment of Guillain- Barré syndrome, there is no significant difference between IVIg, plasma exchange or plasma exchange followed by IVIg. However, for reasons of convenience and safety, IVIg is used as standard treatment in most centers. There is so far insufficient evidence for the use of corticosteroids in the therapy of GBS. In treating CIDP corticosteroids, intravenous immunoglobulin and plasma exchange seem to be equally effective. However, the high costs and relative lack of availability of IVIg, the only short-term benefit and the invasive nature of the plasma exchange procedure, and on the other hand serious long-term side effects of corticosteroids are the most important disadvantages of these treatments and have to be taken into consideration before a decision about therapy can be made. In multifocal motor neuropathy the intravenous immunoglobulin therapy is the only treatment that has been shown to be effective in controlled trials. However, inadequate response in a proportion of patients, high cost and variable availability of IVIg show the need for the search of adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may improve after treatment with chemotherapeutic agents, though the long-term effects are not known. In addition, such treatment modalities may be associated with serious side effect and even severe toxicity. Recent data support the use of a new promising drug: Rituximab, a monoclonal antibody directed against the B cell surface membrane marker CD 20.This article has been adapted from an ENS Teaching Course in Istanbul, Turkey, June 2003.     

Ocular neuropathy in peripheral neuropathies

Ocular movements and coordination require complex and integrated functions of somatic and autonomic nervous systems. Neurological disorders affecting these nervous systems may cause ocular dysfunction involving extraocular muscles and pupils. In this article, the prevalence, clinical presentations, and management of ocular neuropathy related to certain peripheral neuropathies, including diabetic neuropathy, Guillain–Barré syndrome (GBS), chronic inflammatory neuropathies, human immunodeficiency virus (HIV)‐associated neuropathy, and hereditary neuropathies, are examined in detail. Muscle Nerve 46: 681–686, 2012     

Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM)

Identification of risk factors for development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DNA) may help to prevent or modify these complications. The ABCD Trial, a prospective study of diabetic complications, has identified risk factors of the presence and staging of peripheral neuropathy based on neurological symptom scores, neurological disability scores, autonomic function testing and quantitative sensory examination. DSPN is independently associated with diabetes duration [odds ratio (OR) = 1.5 per 10 years], body weight (OR = 1.1 per 5 kg), age (OR = 1.8 per 10 years), retinopathy (OR = 2.3), overt albuminuria (OR = 2.5), height (OR = 1.2 per 10 cm), duration of hypertension (OR = 1.1 per 10 years), insulin use (OR = 1.4), and race/ethnicity [African American vs. non-Hispanic white (OR = 0.4) and Hispanic vs. non-Hispanic white (OR = 0.8)]. DAN is independently associated with diabetes duration (OR = 1.2 per 10 years), body weight (OR = 1.1 per 5 kg), glycosylated hemoglobin (OR = 1.1 per 2.5%), overt albuminuria (OR = 1.6), and retinopathy (OR = 1.8). © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 72–80, 1998.     

Genetically determined neuropathies

There have been major advances in the understanding of the genetically determined neuropathies in recent years. The underlying genetic defects are now known for many of the demyelinating hereditary motor and sensory neuropathies, and linkage data are available for some of the axonal hereditary motor and sensory neuropathies. This has important implications for both diagnosis and genetic counselling in this group of conditions. The genetic defect in most cases of familial amyloid polyneuropathy is also now known. In the most common form of familial amyloid polyneuropathy (FAP), transthyretin-related FAP, liver transplantation has been established as the first definitive treatment for a hereditary neuropathy and should be considered especially in young adult patients. This review will concentrate on the advances in the molecular genetics of the hereditary motor and sensory neuropathies, the hereditary sensory and autonomic neuropathies and the familial amyloid polyneuropathies with particular emphasis on the difficulties in classifying the first group. Received: 29 July 1997 Accepted: 2 September 1997     

Cardiovascular autonomic neuropathy in patients with type 2 diabetes with and without sensorimotor polyneuropathy

Background and Aims

Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN.

Methods

A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition.

Results

Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides.

Interpretation

One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.     

Problems of etiology in femoral neuropathies

29 cases of femoral mononeuropathy are reported. While the clinical features of the femoral neuropathy are easily identified, the etiology is often hard to establish. The cases reported tend to fall into three general categories: 1) cases without major diagnostic difficulties (e.g. diabetic neuropathy); 2) those in which the definite diagnosis results from combined evidence of laboratory and instrumental data (degenerative changes in the lumbar spine, compressions, entrapments, etc.); 3) those in which the negative result of the investigations prevents a positive diagnosis and hence a presumptive etiology (spondylosis, inflammatory process, ischemia of the nerve) may be formulated. Attention is drawn to the favorable course of the condition in the patients of this group.

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Sommario Vengono riportati 29 casi di mononeuropatia femorale. Mentre sul piano semeiologico l'identificazione di una neuropatia femorale risulta agevole, può essere problematico definirne l'eziologia. I casi riportati possono essere inclusi in tre categorie: 1) neuropatie che non presentano particolari difficoltà diagnostiche (es. diabetiche); 2) casi nei quali la diagnosi eziologica scaturisce dall'integrazione di dati clinici e strumentali (es. modificazioni degenerative del rachide lombare, intrappolamenti, etc.); 3) casi nei quali, dato l'esito negativo delle indagini, la diagnosi resta confinata all'ambito delle ipotesi (modificazioni degenerative del rachide lombare, processi infiammatori, ischemia del nervo). Viene segnalato il decorso favorevole dei casi inclusi in quest'ultimo gruppo.

     

Diabetic amyotrophy progressing to severe quadriparesis

Diabetic amyotrophy is a distinctive form of diabetic neuropathy usually characterized by the abrupt onset of pain and asymmetric proximal leg weakness and wasting. Involvement of the upper limbs is unusual, and prognosis is said to be good. We describe two patients, each with type II diabetes mellitus, who presented with diabetic amyotrophy progressing to severe quadriparesis. One patient remains severely disabled. The clinical spectrum of diabetic amyotrophy includes progression to severe quadriparesis.     

Assessment of nerve excitability in toxic and metabolic neuropathies

Abstract   Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.     

Muscle CT in peripheral neuropathies

We studied retrospectively the muscle CT scans of 60 acquired and 40 congenital motor peripheral neuropathies in order to define the diagnostic usefulness of muscle CT in these disorders. Fifty-five percent of the acquired and 72% of the congenital forms showed muscle CT pathological changes correlated to the clinical severity. The typical finding was pure muscle atrophy but several patients also revealed areas of hypodensity. In most of the acquired forms, muscle changes affected both the thighs and legs with a prevalent involvement of the posterior muscles. The congenital forms showed early involvement of the anterior leg muscles. Our study suggests that a CT scan might be useful in evaluating the severity of muscular atrophy, its evolution in time and the prognosis of motor function, in confirming the diagnosis of acquired or congenital neuropathies, and in some cases in defining the phenotypes of congenital forms.     

Sensory neuropathies including painful and toxic neuropathies

In most peripheral neuropathies, dysfunction of motor and sensory nerve fibres is present. However, in some of them either pattern may predominate or be exclusively present. In this review we describe the clinical characteristics of sensory neuropathies, with emphasis on their possible causes. Guidelines are given for the diagnostic approach in these patients and, where possible, suggestions are given for treatment, including symptomatic treatment of painful neuropathies. Received: 1 November 1996ƒAccepted: 23 November 1996     

Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat

We examined the hypothesis that activation of the apoptosis cascade occurs relatively early in diabetes mellitus affecting three distinct neuronal populations that are involved in regulating gut function: (i) dorsal root ganglion (DRG), (ii) vagus nodose ganglion and (iii) colon myenteric plexus. A validated streptozotocin-induced diabetic rat model and age-matched healthy controls were studied. After 4-8 weeks of diabetes the animals were anaesthetized, fixed in situ and the relevant tissues removed. After 1 month of diabetes some animals were treated with insulin for 2 weeks to restore euglycaemia. Apoptosis was measured using immunohistochemical detection of activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)-positive cells in adjacent sections in neurones (PGP 9.5-positive cells). The level of apoptosis was confirmed using double-label assessment of caspase-3 and TUNEL in DRG preparations. Caspase-3 immunoreactive neurones demonstrated a range in staining intensity. When all grades of staining were included, 6-8% of the DRG, nodose ganglia and myenteric neurones were immunoreactive in the preparations from diabetic rats compared with 0.2-0.5% in controls. Neurones staining positive for both caspase-3 and TUNEL accounted for 1-2% of the total neuronal population in all three preparations in diabetic rats compared with 0.1-0.2% in controls (P < 0.05). Insulin treatment reversed the percentage of TUNEL-positive neurones in diabetic rats to control levels. Activation of the apoptosis cascade occurs relatively early in diabetic autonomic neuropathy and may contribute to the pathophysiology of this disorder.     

Analysis of F-wave in metabolic neuropathies: a comparative study in uremic and diabetic patients

Motor nerve conduction study along the entire length of the ulnar and tibialis posterior nerves was carried out in 30 diabetics compared with 30 uremic patients and 30 control subjects. The conduction in the proximal and the distal nerve segments was evaluated by the determination of the M and F latencies, MNCV (between the stimulus sites), FWCV (between the spinal cord and the stimulus sites), and F-ratio (conduction time ratio of proximal to distal segment). In both groups of patients the lower limbs appear much more involved than the upper, where the ulnar nerve is more commonly affected in uremic than in diabetic patients. In diabetic neuropathy the motor conduction abnormalities are diffuse over the total length of the nerve, but more marked distally in the ulnar nerve.     

Transdermal absorption of estradiol in normal subjects and in patients with peripheral neuropathies

Abstract. The relationship of disturbed autonomic skin innervation to altered transdermal absorption in polyneuropathy is not yet clear. In this study we measured serum estradiol in 29 normals and 10 polyneuropathy patients to assess potential differences of estradiol uptake from different skin sites.     

Postprandial hypotension treated with acarbose in a patient with type 1 diabetes mellitus

Abstract Treatment of postprandial hypotension (PPH) is often unsuccessful. We report a case of a type 1 diabetic patient suffering from severely symptomatic PPH. The patient was treated with acarbose and showed definite improvement of both glycemic control and PPH.