Invited review: autonomic dysfunction in peripheral nerve disease.

The autonomic nervous system is affected in most peripheral neuropathies, but only in a small number of conditions, such as diabetes, amyloidosis, Guillain-Barré syndrome, porphyria, and familiar dysautonomia, is autonomic dysfunction of clinical importance. The pathological changes in the peripheral autonomic nervous system are similar to those in the peripheral somatic nerves. Autonomic disturbances are most likely to occur when there is acute demyelination or damage to small myelinated and unmyelinated fibers. Autonomic investigations should include tests of both sympathetic and parasympathetic function. Treatment consists of management of the underlying cause of peripheral neuropathy, physical and pharmacological measures.     

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     

Autonomic nervous system disorders in stroke

Disturbances of the autonomic nervous system are common in patients with various cerebrovascular diseases. They are attributed to damage of the central autonomic network, particularly in the frontoparietal cortical areas and in the brain stem, or to a disruption of the autonomic pathways descending from the hypothalamus via the mesencephalon, pons, and medulla to the spinal cord. The most common clinical problems include abnormalities in heart rate and blood pressure regulation, reflecting cardiovascular autonomic dysfunction, and asymmetric sweating with cold hemiplegic limbs, reflecting changes in the sudomotor and vasomotor regulatory systems. Bladder and bowel dysfunction and impotence are also frequent complaints after stroke, but the present knowledge concerning their prevalence and clinical significance is still limited. Cardiovascular autonomic dysfunction, which is mainly related to increased sympathetic activity, is most evident in the acute phase of stroke, whereas other autonomic disorders, such as abnormal sweating, are long-standing or even irreversible. In addition to the well-established sympathetic hyperfunction, abnormalities of the parasympathetic nervous system may also contribute to the autonomic imbalance after stroke. Reliable recognition of autonomic dysfunction using quantitative analysis methods is important, because these disturbances are not only subjectively disabling and uncomfortable, but they may also be prognostically unfavorable. Moreover, quantitative measurements also form the ground for successive treatment of various stroke-related autonomic disorders.     

Multiple system atrophy. Clinical aspects, pathophysiology, and treatment

Progressive autonomic failure is a clinical syndrome of autonomic dysfunction that may occur in isolation as in idiopathic orthostatic hypotension (IOH) or in association with a central neurologic disorder, multiple system atrophy (MSA). MSA and IOH can be distinguished on the basis of biochemical and pharmacologic tests. Plasma norepinephrine levels are low in IOH and normal in MSA; neither group increases the plasma norepinephrine level adequately in response to postural change. Both MSA and IOH manifest an exaggerated pressor response to administered norepinephrine. However, only patients with IOH have true adrenergic receptor supersensitivity. The autonomic dysfunction in IOH primarily involves the peripheral autonomic neurons whereas the defect in MSA is the failure to activate appropriately an intact distal sympathetic nervous system. Neuropathologic studies reveal a multisystem degeneration in MSA; the few postmortem examinations of the central nervous system in IOH reveal lesions confined to the intermediolateral columns of the spinal cord. Orthostatic hypotension may be treated with a number of medications although supine hypertension limits the usefulness of these drugs. Further development and testing of a sympathetic neural prosthesis may help to resolve this therapeutic dilemma. Only the parkinsonian features in MSA respond to treatment with anticholinergic drugs.     

Paraneoplastic peripheral neuropathies

Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.     

Acute autonomic and sensory neuropathy: report of an autopsy case

Summary A 46-year-old woman presented acute sensori-motor neuropathy of the Guillain-Barré type, followed by a protracted course of profound autonomic and sensory dysfunction. Tests of autonomic functions showed denervation hypersensitivity. Neuropathologically, the trigeminal sensory nuclei, solitary nucleus, the dorsal columns of the spinal cord and dorsal spinal roots showed severe degeneration. Degeneration was found both in the preganglionic (intermediolateral cell columns of the spinal cord) and postganglionic (sympathetic ganglion and celiac ganglion) neurons of the sympathetic nervous system, and the preganglionic (dorsal motor nucleus of the vagus) and postganglionic (Auerbach's plexus) neurons of the parasympathetic nervous system.     

Peripheral neuropathy as the presenting feature of multiple system atrophy

The authors report a case of multiple system atrophy (MSA) with an onset as a peripheral nerve involvement. Their patient, a 55-year-old man, had a 3-year history of distal weakness and atrophy in upper limbs with dysesthesia in the feet. Other identifiable causes of peripheral neuropathy were ruled out. The authors postulate that peripheral nervous system impairment can anticipate the typical appearance of MSA, and they suggest that, in peripheral neuropathies with autonomic system dysfunction, after excluding main causes of autonomic neuropathy, MSA may need to be suspected.     

Quantitative studies of autonomic function

Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity.     

Peripheral neuropathy associated with mitochondrial disease in children

Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease.     

Treatment of peripheral neuropathies with neutrotrophic factors: animal models and clinical trials

In vitro experiments and works with knock-out mice have demonstrated the physiological importance of neurotrophic factors (NF) in the development and the survival of peripheral nervous system neurons. Therefore, NF may be useful in the treatment of peripheral neuropathies. These pathologies may be more amenable than central nervous diseases to the systemic delivery of NF. Indeed, NF can readily access peripheral nerves from blood whereas penetration into the central nervous system is limited by the blood-brain barrier. The objectives of NF treatment are: 1) to compensate a putative deficiency of NF associated with the pathogenesis of some neuropathies, such as diabetic neuropathy; 2) to stop or slow disease progression by acting on the biochemical pathways involved in the neurodegenerative cascade; and 3) to enhance the physiological compensatory mechanism of axonal sprouting. The efficacy of treatment with NF has been demonstrated in animal models mimicking various neuropathies, such as neuropathies related to diabetes or treatment with chemotherapeutic agents. However, a phase 3 trial in diabetic neuropathy and a phase 2 trial in HIV-related neuropathy have failed to demonstrate any substantial effect of treatment with NGF. In this review, we discuss the factors that may explain these negative results. A major limitation of systemic administration is the poor bioavailability of NF due to their short half-life. Alternative modes of delivery may be more appropriate than systemic administration of the recombinant protein. In particular, muscular-based gene therapy allows the delivery of sustained levels of neurotrophic factor into the circulation. This strategy has shown to be effective in animal models of motor and sensory neuropathies. Another promising treatment is the use of small molecules that induce the endogenous synthesis of NF, such as xaliprodene or 4-methylcathecol.     

Autonomic peripheral neuropathy

Most generalized peripheral polyneuropathies are accompanied by clinical or subclinical autonomic dysfunction. There is a group of peripheral neuropathies in which the small or unmyelinated fibers are selectively targeted. In these neuropathies, autonomic dysfunction is the most prominent manifestation. The features associated with an autonomic neuropathy include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor autonomic function.     

Disease mechanisms in hereditary sensory and autonomic neuropathies

Inherited peripheral neuropathies are common monogenically inherited diseases of the peripheral nervous system. In the most common variant, i.e., the hereditary motor and sensory neuropathies, both motor and sensory nerves are affected. In contrast, sensory abnormalities predominate or are exclusively present in hereditary sensory and autonomic neuropathies (HSAN). HSAN are clinically and genetically heterogeneous and are subdivided according to mode of inheritance, age of onset and clinical evolution. In recent years, 6 disease-causing genes have been identified for autosomal dominant and recessive HSAN. However, vesicular transport and axonal trafficking seem important common pathways leading to degeneration of sensory and autonomic neurons. This review discusses the HSAN-related genes and their biological role in the disease mechanisms leading to HSAN.     

The cardiac R-R variation and sympathetic skin response in the intensive care unit

BACKGROUND AND PURPOSE: The central and peripheral nervous systems are often affected in intensive care unit (ICU) patients, especially those with prolonged assisted ventilation and sepsis or systemic inflammatory response syndrome (SIRS). The autonomic nervous system, however, has been under-investigated in such patients. We evaluated autonomic nervous system (ANS) function in 29 ICU patients with various neurological disorders. METHODS: Testing involved cardiac R-R variation (CRRV) as an index of parasympathetic function and the sympathetic skin response (SSR) for sympathetic assessment. RESULTS: Only those 8 patients with sepsis-related neuropathy or encephalopathy had abnormal CRRV, while the SSR was absent in all but 2 patients. CONCLUSIONS: Our preliminary study revealed a high incidence of autonomic dysfunction in ICU patients with various neurological disorders.     

The neurologic manifestations of the acute porphyrias

The porphyrias are diseases characterised by accumulation of porphyrins and porphyrin precursors owing to enzymatic deficiencies of the haem synthetic pathway. In the acute hepatic porphyrias accumulation of porphyrin precursors, in particular delta-aminolaevulinic acid (ALA), cause dysfunction of the central, peripheral and autonomic nervous systems. This leads to the characteristic clinical findings of abdominal pain, neuropsychiatric symptoms and neuropathy. The exact pathogenic mechanism is not clear but evidence to date suggests both direct toxic effects of ALA and intracellular metabolic derangement contribute to the neurologic disorders. This review explores the mechanisms of neural dysfunction in the acute porphyrias and the resultant clinical features of an acute attack.     

Inflammatory neuropathies

Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP.     

Autonomic dysfunction according to disease progression in Parkinson's disease

BackgroundAlthough autonomic dysfunction is common in patients with Parkinson’s disease (PD), few data are available regarding its pattern and quantitative severity with increasing Hoehn and Yahr (H&Y) stage. We conducted autonomic function tests to quantify autonomic dysfunction in PD patients and to elucidate its possible relationship with disease progression.MethodsWe performed autonomic function tests including Valsalva ratio, heart rate response to deep breathing, quantitative sudomotor axon reflex test, and head-up tilt test in 66 patients with PD. We compared clinical characteristics and results of autonomic function tests between stages, and correlated the proportion of abnormal patients in each test with their H&Y stage. In addition, logistic regression analyses were conducted to examine the contribution of increasing H&Y stage to impairments of each domain of the autonomic nervous system.ResultsWe found that PD patients with higher disease stage tended to have impairments in cardiovagal and sudomotor domains of the autonomic nervous system. Cardiovagal function was the domain most influenced by disease progression. Our findings also demonstrated that the pattern of sudomotor impairment in PD was similar to that in patients with peripheral autonomic neuropathy.ConclusionsOur study demonstrates that autonomic dysfunction is not only common in early stage PD but it increases in severity with increasing disease stage. Given that the patterns of sudomotor impairments in PD are similar to those in peripheral neuropathy, our data support a previous hypothesis that pathophysiology of PD involves both the central and peripheral nervous systems.     

屈昔多巴的临床应用进展

屈昔多巴是一种人工合成的去甲肾上腺素前体药物,当交感神经系统受损时,屈昔多巴在L-芳香族氨基酸脱羧酶的作用下,在外周和中枢神经通过脱羧作用转化为去甲肾上腺素,从而使神经系统去甲肾上腺素水平升高。1989年,日本便将屈昔多巴运用在神经源性体位性低血压的治疗中,但是其未在欧洲或美国使用,直到2014年美国FDA批准屈昔多巴治疗有症状的直立性低血压,其次是原发性自主神经病变、多巴胺-β-羟化酶缺乏症或非糖尿病自主神经病变。2012年1月,中国重庆圣华曦药业股份有限公司3.1类新药屈昔多巴胶囊(商品名:善为)获批上市,是屈昔多巴在国内的首次应用。屈昔多巴在治疗体位性低血压、步态障碍以及透析性低血压的疗效确切,安全性良好。文中就屈昔多巴的药动学特性、作用机制、临床效果以及耐受性研究进行综述。     

Impaired ascendant central pathways conduction in impotent diabetic subjects

OBJECTIVES: Diabetic impotence is generally due to peripheral neuropathy, but a central pathway impairment has also been suggested. We evaluated somatosensory transmission in a group of impotent diabetic men to assess the role of central nervous system (CNS) involvement. MATERIALS AND METHODS: Somatosensory evoked potentials (SEPs) of pudendal (pdn) and posterior tibial (ptn) nerves were recorded in 74 patients. Type and duration of diabetes, severity of sexual dysfunction, medium term metabolic control, occurrence of microangiopathic chronic complications and autonomic neuropathy were evaluated. RESULTS: Our data show an impairment of central conduction times in pdn (25.7%) and ptn (39.2%) greater than peripheral nervous impairment (pdn 12.2%, ptn 8.1%), in impotent diabetic patients without any further major complication. Central nervous conduction delay resulted to be correlated with poor glycemic control. Significant evident autonomic dysfunction was found only in a minority of cases. CONCLUSION: Our data might suggest that altered conduction along CNS and somatic peripheral neuropathy might develop independently. We confirm the hypothesis of a "central diabetic neuropathy" and suggest that central sensory pathways involvement, not related to peripheral impairment, could play a role in the pathogenesis of erectile dysfunction in diabetic patients.     

Autonomic features in Parkinson disease

Nonmotor symptoms such as autonomic and neuropsychiatric dysfunctions, are commonly seen in Parkinson disease (PD). Recent studies have shown that PD is accompanied by cardiac sympathetic denervation and constipation even in the early stage. Neuropathological studies confirmed changes in the cardiac sympathetic nerves and the gastrointestinal tract. These findings suggest that PD neuropathology may occur first in the peripheral autonomic pathways and extend to the central autonomic pathways, in agreement with the "Braak theory". This article will reviews the symptoms and pathophysiology of gastrointestinal dysfunction, urinary disturbance, sexual dysfunction, sweating dysfunction, pupillary autonomic dysfunction, and orthostatic and postprandial hypotension in PD patients, and discuss to organ selectiveness in autonomic dysfunction in PD.     

Autonomic involvement in Guillain–Barre syndrome: A review

Autonomic neuropathy is an important and common complication of Guillain-Barré syndrome (GBS). Manifestations be present in cardiovascular, sudomotor, gastrointestinal and other systems involving both sympathetic and parasympathetic fibers. Some apparently selective acute autonomic neuropathies may be subvarieties of GBS. Experimental work in animal models, pathological studies of GBS patients, and autonomic function studies have provided some help in the understanding of this complication. In managing GBS patients with autonomic dysfunction there are important practical considerations that can improve their care. In this article we review the literature on autonomic neuropathy in GBS and propose a management scheme to accommodate it in the overall treatment of the neuropathy. © 1994 John Wiley & Sons, Inc.