Autonomic neuropathy, II: Specific peripheral neuropathies

JOURNAL

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NEUROLOGICAL SCIENCES

ELSEVIER

Journalof theNeurologicalSciencesI38 ( 1996)1- I3

Review article

Autonomic neuropathy, II: Specific peripheral neuropathies Alan J. McDougall, James G. McLeod * Depamnent of Medicine, Unicersity of Sydney and Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, Australia

Received24 July 1995;revised16 November1995;accepted16 November1995

Abstract Autonomic dysfunction is a common complication of peripheral neuropathies. It is often of little clinical importance, but some conditions may causeprofound disturbance of autonomic function. These conditions include acute dysautonomia, diabetes,primary and familial amyloidosis, Guillain-Barr6 syndrome, porphyria, and someinherited neuropathies.A wide range of neuropathiesare associated with lesser degrees of autonomic dysfunction. These include hereditary neuropathies, and neuropathies associated with metabolic disturbances,alcohol abuse,malignancy, medications, infections, and connective tissue disorders. Keywords:

Autonomicdysfunction;Peripheralneuropathy;Anatomy;Pathophysiology; Investigation;Treatment

1. Introduction Some degree of autonomic dysfunction occurs in most peripheral neuropathies ( and Table 1). For practical purposes, they can be classified into those in which the autonomic dysfunction is frequently of clinical importance, and those in which it is usually of minor importance.

2. Peripheral function

neuropathies

with severe autonomic dys-

2. I. Acute dysautonomia This condition was first described by Young et al. (1969). It comprises acute or subacute severe autonomic failure affecting both sympathetic and parasympathetic nerve function with relative sparing of peripheral somatic nerves (Suarez et al., 1994). The condition affects both sexes and all ages. There are no known familial or hereditary factors. There may be an antecedent viral infection, such as herpes simplex, infectious mononucleosis or rubella. The onset of the illness may be acute or gradual with symptoms of postural hypotension, blurred vision, dry mouth and eyes, abdominal pain, bloating, nausea, vomit-

* Correspondingauthor.Departmentof Medicine,University of SydCamperdown, N.S.W.2050,Australia.Fax: (+61-2) 351-4018.

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ing, constipation or diarrhoea, urinary retention, impotence, and loss of sweating. More recently, it has been recognised that sensory nerve fibres may sometimes be involved resulting in mild sensory abnormalities, such as paraesthesiae, itching, and distal impairment of pain and temperature perception. Investigations show widespread abnormalities of autonomic function. Nerve conduction studies may be normal or show mild impairment of sensory and motor conduction. Cerebrospinal fluid protein is elevated in some cases. Recovery is gradual and may be incomplete. One patient recovered fully after 4 months, another showed only partial recovery after 16 years (Appenzeller and Kornfeld, 1973; Hopkins et al., 1974). Cases of pure cholinergic dysautonomia have been described (Hopkins et al., 1980). In this condition, the clinical findings are as described above with the exception of the absence of postural hypotension. There is also a very rare syndrome of pure sympathetic failure with postural hypotension and impairment of sweating. Some cases of this syndrome may be less severe or restricted to parts of the autonomic nervous system, and may be manifested as the postural orthostatic tachycardia syndrome or neurogenie gastrointestinal motility disorders (Schondorf and Low, 1993). The aetiology of the condition is uncertain. It has been postulated that acute dysautonomia is a variant of the Guillain-Barr6 syndrome selectively affecting the autonomic fibres. However axonal degeneration with loss of

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A.J. McDougall, J.G. McLeod/ Journal of the Neurological Sciences 138 (1996) l-13

small myelinated and unmyelinated fibres in the sural nerve has been described (Ferrer et al., 1991). In another case, there were numerous lymphocytic infiltrates in autonomic and sensory ganglia, with less prominent infiltrates in the spinal roots, spinal cord and brainstem (Stall et al., 1991). These reports suggest that acute dysautonomia may be a heterogenous condition. 2.2. Diabetes Diabetes mellitus is the most common cause of autonomic neuropathy. The true incidence and prevalence of diabetic autonomic neuropathy are unknown (Dyck et al., 1993; Ross, 1993). Methodological problems account for much of this uncertainty. The prevalence is much higher if autonomic test results rather than clinical symptoms are used as diagnostic criteria. Most published series show that 20-70% of diabetic subjects have abnormal autonomic function tests (Hilsted and Low, 1993). The likelihood of autonomic failure increases with the level of hyperglycaemia, the duration of diabetes, the age of the subject, and male gender (DCCT Research Group, 1988, 1993). The pathological changes found in the autonomic nervous system consist of both axonal degeneration and segmental demyelination (Low et al., 1975b; Guo et al., 1987). The pathogenesis of diabetic neuropathy remains unclear, and a number of different mechanisms have been proposed. These include metabolic dysfunction (sorbitol accumulation, myo-inositol deficiency, non-enzymatic protein glycosylation, impaired axoplasmic transport), ischaemia, immune mechanisms, disturbances of growth factors, and genetic predisposition. The clinical features of diabetic autonomic neuropathy include postural hypotension, impaired heart rate control, impaired oesophageal and gastric motility, constipation, diarrhoea, bladder disturbances, impotence, impaired sweating, and pupillary abnormalities. Postural hypotension is the most common cardiovascular symptom of autonomic neuropathy. The reported incidence of this symptom varies from 25% to less than 1% depending upon patient selection criteria. Postural hypotension results from degeneration of sympathetic neurones that supply the splanchnic mesenteric vessels as well as neurones supplying other vascular areas and the heart and afferent fibres from baroreceptors (Low et al., 1975b). Impairment of heart rate control reflecting vagal involvement is more common and occurs earlier in the course of diabetes than the sympathetic changes causing postural hypotension (Ewing et al., 1980a). Symptomatic gastrointestinal problems in diabetics are uncommon (Niakan et al., 1986; Hilsted and Low, 1993). Oesophageal motility may be abnormal due to damage to the vagus nerves and enteric nervous system. However clinical manifestations are rare and usually consist of only mild dysphagia or heartburn. Abnormalities of gastric

function include delayed gastric emptying, slow peristalsis, gastric dilatation, and achlorhydria. Symptoms include anorexia, persistent fullness after meals, nausea, and vomiting. Abnormalities of motor function can be found in 20-30% of patients, but only some of these patients will be symptomatic. Constipation is the most common intestinal manifestation of diabetic autonomic neuropathy. It results from extensive denervation of the colon. Diabetic diarrhoea is a very distressing symptom of diabetic autonomic neuropathy. It can be paroxysmal, sudden, explosive, uncontrollable and often nocturnal. Symptoms usually last from a few hours to a few days and often remit. Malnutrition does not occur. The exact cause of diabetic diarrhoea is uncertain. Other causes of diarrhoea, such as chronic pancreatitis, gluten intolerance and infection, should be excluded. Diabetic diarrhoea may respond to treatment with the somatostatin analogue octreotide or with clonidine (Fedorak et al., 1985; Nakabayashi et al., 1994). Faecal incontinence may be present in patients with diabetic rectal neuropathy. This often occurs in the presence of severe diarrhoea, but may be an independent problem. Bladder dysfunction is a common problem with a prevalence of 20-80% in different studies. Most patients with a diabetic neurogenic bladder have other long-term diabetic complications including impotence. The onset of symptoms is insidious despite significant residual urine volume. Later symptoms include urinary hesitancy, straining, weakness of stream, and sensation of incomplete bladder emptying. Overflow incontinence and secondary infections also occur. Urinary tract infections may be severe and even fatal, and may also hasten the decline in kidney function (Edmonds and Watkins, 1992). Residual urine measurements and cystometry or urodynamic studies are useful investigations. Impotence is a common problem and may be the first manifestation of autonomic failure. It results from damage to both parasympathetic and sympathetic innervation of the corpora cavemosa. Diminished penile blood flow due to accelerated atherosclerosis may also contribute. Abnormalities of sweating are well described. The most common sweating deficit is over the lower limbs in a stocking distribution. Patients with mononeuropathies or plexopathies may have absent sweat responses over the cutaneous distribution of the nerve. Postgustatory sweating may occur over the forehead, face, and neck. It is thought to be due to aberrant sympathetic nerve regeneration affecting the superior cervical ganglion. Pupillary abnormalities occur with diabetic autonomic neuropathy. These changes are usually associated with cardiovascular and other manifestations of autonomic dysfunction. The usual finding is small pupils which fail to dilate normally in darkness. The presence of clinical autonomic neuropathy is associated with a worse prognosis for long-term survival. Ewing et al. (1980b) reported a mortality rate of 50% at

A.J. McDougall, J.G. McLzod/Journal Table I Classification

of peripheral autonomic disorders a

Acute dysautonomia Acute pandysautonomia b Acute cholinergic dysautonomia b Acute sympathetic dysautonomia b Hereditary neuropathies Familial amyloid polyneuropathy ’ Hereditary sensory and autonomic neuropathy type III (Riley-Day syndrome) b Hereditary sensory and autonomic neuropathy type IV (Swanson type) b Dopamine-p-hydroxylase deficiency b Hereditary sensory and autonomic neuropathy types I, II, and V Hereditary motor and sensory neuropathy types I and II (Charcot-Marie-Tooth disease) Fabry’s disease Navajo neuropathy, type B Inflammatory neuropathies Acute inflammatory polyneuritis (Guillain-Barre syndrome) b Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Infections Leprosy Human immunodeficiency virus (HIV) infection Chagas’ disease Diphtheria Lyme disease Metabolic disorders Diabetes b Primary amyloidosis b Acute intermittent and variegate porphyria b Chronic renal failure Chronic liver disease Vitamin B I? deficiency Alcohol abuse Malignancy Direct infiltration of nerves Paraneoplastic dysautonomia Subacute sensory neuronopathy Enteric neuronopathy Lambert-Eaton myasthenic syndrome Connective tissue disorders Rheumatoid arthritis Systemic lupus erythematosus Mixed connective tissue disease Sjiigren’s syndrome Inflammatory bowel disease Crohn’s disease Ulcerative colitis Chronic lung disease Multiple symmetric lipomatosis (Madelung’s disease) Drugs and toxins Vincristine Cisplatin Taxol Amiodarone Perhexiline Thallium Arsenic Inorganic mercury Organic solvents Hexacarbons Acrylamide Vacor ’ Modified from McLeod (1993). b Autonomic dysfunction frequently clinically

important.

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2.5 years. Most patients died of renal failure. Another study (O’Brien et al., 199 1) found a 5-fold increase in mortality over 5 years in diabetics with autonomic neuropathy (27%) compared to those without neuropathy (5%). Autonomic neuropathy is also associated with an increased incidence of silent myocardial infarction and sudden death (O’Sullivan et al., 1991). However, the prognosis for diabetics with abnormal autonomic function tests, but no clinical symptoms, has been shown to be good. Sampson et al. (1990) found no difference in mortality over 10 years in this group compared to diabetics with no autonomic function abnormalities. A large controlled clinical trial (DCCT Research Group, 1993) has shown that intensive insulin therapy with the goal of maintaining blood glucose concentrations close to the normal range can delay the onset and slow the progression of long-term diabetic complications. In patients with no neuropathy at the onset of the trial, intensive therapy reduced the appearance of neuropathy at 5 years by 69%. The rates of neuropathy were 3% in the intensive therapy group and 10% in the conventionally treated (or control) group. These figures include clinical sensorimotor neuropathy, autonomic nerve tests, and nerve conduction studies; similar improvement was seen for all 3 indices. In contrast to these results, a number of studies have failed to show significant benefit from improved glycaemic control in the progression of established autonomic or peripheral neuropathy (Service et al., 1983; The St Thomas’s Diabetic Study Group, 1986). A number of trials of aldose reductase inhibitors have shown a slight benefit in halting or slowing the progression of autonomic neuropathy (Sundkvist et al., 1987; Giugliano et al., 1993). The clinical role of these agents in still uncertain. Pancreatic or pancreatic and renal transplantation have been shown to stop progression of autonomic neuropathy and to improve peripheral somatic neuropathy (Kennedy et al., 1990; Aridge et al., 1991). 2.3. Amyloidosis

Autonomic dysfunction occurs in most types of primary and hereditary amyloid disease (Hersch and McLeod, 1987). Primary amyloidosis is associated in about 20% of cases with an autonomic neuropathy which may accompany or sometimes precede the peripheral somatic neuropathy. The symptoms are often disabling, the most prominent of which are postural hypotension, genitourinary disturbances (impotence, incomplete bladder emptying, incontinence) and gastrointestinal disturbances (dysphagia, vomiting, diarrhoea, constipation, incontinence). Pupillary abnormalities and widespread anhidrosis may be present on examination. Other clinical findings may be a distal, painful sensory neuropathy with impaired pain and temperature sensation, carpal tunnel syndrome, macroglos-

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sia, weight loss, and renal impairment. Investigations show widespread abnormalities of autonomic function. Amyloid deposits may be found with nerve, skin or rectal biopsy. Autonomic dysfunction is attributable to the predominant loss of unmyelinated and small myelinated fibres in the peripheral nerves as well as loss of cells in the intermediolateral columns of the spinal cord. Widespread deposits of amyloid are found in the autonomic nerves and ganglia (Fig. 1). The clinical course is one of steady progression and treatment is symptomatic. Autonomic neuropathy occurs in all cases of familial amyloid polyneuropathy type I (the Portuguese variety, FAP I). The condition is due to a point mutation in the transthyretin gene and is dominantly inherited. Symptoms usually begin in the third or fourth decades. The clinical features are similar to primary amyloidosis although progression is slower. One report suggests that liver transplantation may stop progression of neurological dysfunction in FAP (Holmgren et al., 1993). Type II FAP (the Indiana form) is also associated with an autonomic and sensory neuropathy. Type III (the Iowa form) shows less conspicuous autonomic involvement (Thomas, 1992). 2.4. Guillain-Barre’

syndrome

Autonomic disturbances are well recognised (Tuck and McLeod, 1981; Zochodne, 1994). There may be autonomic over- and underactivity. Cardiovascular abnormalities are most common. These include fixed tachycardia, electrocardiograph abnormalities, labile arterial pressure, hypertension, postural hypotension, bradyarrhythmias (including

of the Neurological

Sciences 138 (1996) I-13

asystole), and tachyarrhythmias. Patients may be very sensitive to small doses of vasoactive drugs, possibly due to denervation supersensitivity. Disturbances of sweating are also common. Genitourinary and gastrointestinal abnormalities are less frequent. The variable nature of autonomic dysfunction depends upon the anatomical site of the demyelinating lesions; e.g. afferent fibres in the vagus and glossopharyngeal nerves, or efferent fibres in the vagus and preganglionic sympathetic nerves. Pathological studies have demonstrated demyelinating lesions in the glossopharyngeal and vagus nerves and in the sympathetic chains and white rami communicantes (Matsuyama and Haymaker, 1967; Asbury et al., 1969). The severity of autonomic involvement is not closely related to the degree of motor or sensory disturbance (Tuck and McLeod, 1981). In most patients, the autonomic abnormalities are not serious, but in some patients, they may be life threatening. Postural hypotension may lead to syncope and ischaemic brain damage in a paralysed patient left in an upright position, paroxysms of severe hypertension may occur, and sudden death due to cardiac arrhythmia or asystole has been reported. Winer and Hughes (1988) studied one hundred patients and reported 11 patients developing serious arrhythmias and 7 deaths. The management of autonomic dysfunction in the Guillain-Barre syndrome is discussed by Zochodne (1994). 2.5. Porphyria

Dysautonomia is common in acute intermittent and variegate porphyria. The rarer conditions of hereditary

Fig. 1. Amyloid deposits (arrows) in thoracic sympathetic trunk of a patient with primary amyloidosis. (From McLeod (1992) with permission of Oxford Unib rersity Press, Oxford.)

A.J. McDougall, J.G. McLeod/ Journal of the Neurological

coproporphyria and &amino laevulinic acid dehydratase deficiency may also cause autonomic neuropathy (Stewart and Hensley, 198 1; Thomas, 1992). Autonomic overactivity predominates over autonomic failure, although both are present and often coexist. Symptoms of autonomic overactivity include abdominal colic, hypertension, and tachycardia. Postural hypotension may occur, although hypertension is more common. Other autonomic changes include nausea and vomiting, bowel and bladder disturbances (severe constipation is common), pupillary abnormalities, and either anhidrosis or hyperhidrosis. Autonomic abnormalities, such as persistent tachycardia or hypertension, may precede other manifestations of an attack, such as peripheral neuropathy (Ridley, 1969). Autonomic studies have demonstrated abnormalities of both sympathetic and parasympathetic cardiovascular function during an acute episode. Mild parasympathetic cardiovascular dysfunction may be present between acute episodes and in latent asymptomatic acute intermittent porphyria (Yeung Laiwah et al., 1985). Pathological changes have been demonstrated in vagus and sympathetic nerves as well as in the brainstem and spinal cord neurones (Hierons, 1957; Perlroth et al., 1966). The peripheral nerve changes resemble a primary axonopathy (Cavanagh and Mellick, 1965). 2.6. Familial dysautonomia (Riley-Day type Ill!

syndrome, HSAN

This is an autosomal recessive syndrome (chromosome 9) with autonomic and sensorimotor nerve involvement. Most reported cases have occurred in Ashkenazi Jews. It presents in infancy with failure to thrive, poor feeding and episodes of unexplained fever. Autonomic findings include lability of blood pressure, postural hypotension, periodic vomiting, bowel and bladder disturbances, impaired temperature control, hyperhidrosis, transient blotching of the skin, and decreased lacrimation. Other findings are absent fungiform papillae of the tongue, sensory abnormalities with a marked reduction in cutaneous pain and temperature appreciation, hyporeflexia, impaired motor skills, kyphoscoliosis, Charcot’s joints, and variable cognitive abnormalities (Riley et al., 1949; Brunt and McKusick, 1970). Nerve biopsies show a loss of unmyelinated and small myelinated fibres (Aguayo et al., 197 1). There are also reduced numbers of neurones in the autonomic, dorsal root, and trigeminal ganglia (Pearson et al., 1971). 2.7. Hereditary sensory and autonomic neuropathy type IV (Swanson type, HSAN type IV) This is an autosomal recessive disorder affecting infants. The clinical features are: recurrent high fevers due to truncal anhidrosis, painless injuries of the extremities and

Sciences 138 (1996) 1-13

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oral structures, lack of pain sensation, preserved deep tendon reflexes, and mild mental retardation (Ouvrier and McLeod, 199 1). There is a loss of small myelinated and unmyelinated nerve fibres (Swanson et al., 1965). 2.8. Dopamine-P-hydroxylase

deficiency

This is a recently recognised condition of sympathetic adrenergic failure with preserved sympathetic cholinergic and parasympathetic function (Robertson et al., 1986). It is due to congenital absence of the enzyme dopamine-ghydroxylase. This enzyme is part of the catecholamine biosynthetic pathway and catalyses the conversion of dopamine to noradrenaline, and in its absence, the synthesis of both noradrenaline and adrenaline is blocked. The clinical features are severe postural hypotension, partial ptosis (due to involvement of Muller’s muscle), nasal stuffiness (due to lack of sympathetic vasoconstriction), retrograde ejaculation and reduced vaginal secretions. Symptoms begin in childhood. There is usually no family history of the condition (Mathias et al., 1990). Autonomic function tests show sympathetic adrenergic failure with postural hypotension and impaired blood pressure responses to other tests. Parasympathetic tests of heart rate control and sympathetic cholinergic sweating tests are normal. Plasma catecholamine measurements show undetectable levels of noradrenaline and adrenaline with abnormally elevated levels of dopamine. Immunohistochemical tests of skin biopsies can demonstrate the absence of the enzyme. Oral administration of the drug b,L-dihydroxyphenylserine causes dramatic improvement (Biaggioni and Robertson, 1987; Man In’t Veld et al., 1987). This drug is converted directly to noradrenaline by the enzyme DOPAdecarboxylase. It therefore bypasses the absent DBH enzymatic step and restores adrenergic function.

3. Peripheral function

neuropathies

with minor autonomic dys-

Autonomic abnormalities of a minor degree have been reported in a large number of peripheral neuropathies. The main findings are given below. 3.1. Hereditary neuropathies 3.1.1. Charcot-Marie-Tooth

disease (HMSN types I and

II)

There are abnormalities in distal limb vasomotor and sudomotor function. Symptoms include coldness, peripheral cyanosis, trophic ulceration, and anhidrosis of the extremities. Autonomic investigations show abnormal skin vasomotor reflexes, sympathetic skin responses and impairment of sweating over the distal limbs with the thermal sweat test (Jammes, 1972). Pupillary abnormalities are also

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found (Bird et al., 1984). There are reports of abnormal cardiovascular reflex function (Jammes, 1972; Bird et al., 1984; Solders et al., 1991). However, Ingall and McLeod (1991) studied 15 patients and found no significant abnormalities in cardiovascular autonomic function tests. 3.1.2. Hereditary sensory and autonomic neuropathies The following autonomic abnormalities have been reported (Ouvrier and McLeod, 199 1; Thomas, 1992). HSAN I (hereditary sensory radicular neuropathy) Impairment of sweating over distal extremities, no cardiovascular autonomic changes. HSAN II (hereditary sensory neuropathy) Distal anhidrosis, episodic fever, impotence and neurogenic bladder may occur (Nukada et al., 1982). HSAN V (congenital sensory neuropathy with selective loss of small myelinated fibres) Pupillary abnormalities, reduced Valsalva ratio, normal thermal sweat test (Low et al., 1978). Navajo neuropathy, type B (Nacajo neuropathic arthropathy) Anhidrosis and heat intolerance (Johnsen et al., 1985). A number of other inherited sensory neuropathies, some with autonomic dysfunction, have been described (see Ouvrier and McLeod, 1991). 3.1.3. Fabry’s disease This is an X-linked disorder with deficiency of the enzyme a-galactosidase A causing accumulation of glycolipids, particularly ceramide trihexose. Glycolipid accumulation is found in autonomic neurones and there is a loss of unmyelinated and small myelinated nerve fibres (Ohnishi and Dyck, 1974). Autonomic symptoms include impaired sweating leading to complete anhidrosis, gastrointestinal dysfunction with indigestion, nausea, belching, oesophageal reflux, abdominal pain, flatus, and diarrhoea. Autonomic tests reveal pupillary abnormalities, abnormal tear and saliva production, widespread anhidrosis, reduced cutaneous flare response for scratch and intradermal histamine, and abnormal colonic motility (Cable et al., 1982). Cardiovascular autonomic tests are normal. There is one case report of a female carrier of Fabry’s disease with postural hypotension (Mutoh et al., 1988). 3.2. Metabolic disorders 3.2.1. Chronic renal failure Autonomic dysfunction occurs in both predialysis and haemodialysis patients. Parasympathetic cardiovascular abnormalities are more common than sympathetic cardiovascular changes (Vita et al., 1990). Impaired baroreflex function is also reported (Bondia et al., 1988). In some patients, severe hypotension may occur during haemodialysis. These patients have normal sympathetic efferent function, but impaired baroreflex sensitivity (Nies et al., 1979; Niak et al., 1981). There may be factors other

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than autonomic neuropathy contributing to the severe hypotension in these patients. Renal transplantation may result in improvement in the autonomic abnormalities (Mallamaci et al., 1986). 3.2.2. Chronic liver disease Cardiovascular autonomic dysfunction occurs in both non-alcoholic and alcoholic chronic liver disease (see below). In non-alcoholic chronic liver disease parasympathetic abnormalities are more common (45% of patients) than sympathetic changes (12% of patients) (Thuluvath and Triger, 1989). Patients may have abnormal autonomic function without evidence of a peripheral neuropathy. A similar pattern of cardiovascular autonomic dysfunction is found in individual diseases causing liver damage, such as primary biliary cirrhosis (Hendrickse and Triger, 1993). The prevalence and severity of cardiovascular autonomic dysfunction is related to the severity of hepatic damage and is independent of aetiology (Hendrickse and Triger, 1992). The presence of autonomic neuropathy is associated with a worse long-term prognosis (Hendrickse et al., 1992). 3.2.3. Vitamin B,, deficiency Postural hypotension may rarely be a presenting feature of pernicious anaemia (White et al., 1981). The postural hypotension resolves quickly with vitamin B,, therapy, often in the absence of improvement in the peripheral somatic neuropathy. The peripheral nerve pathological changes are those of axonal degeneration (McCombe and McLeod, 1984). Because of the rapid improvement of postural hypotension following treatment, the responsible lesion may be biochemical and functional rather than structural (White et al., 1981). 3.3. Alcohol abuse Clinical manifestations of autonomic dysfunction except for impaired sweating distally are unusual in uncomplicated alcoholic peripheral neuropathy (Low et al., 1975a; Duncan et al., 1980). Postural hypotension may occur in severely affected cases or in Wemicke’s encephalopathy which is associated with central abnormalities of autonomic control (Birchfield, 1964; Novak and Victor, 1974). Abnormalities of cardiovascular parasympathetic tests are common, but cardiovascular sympathetic changes are much less frequent (Duncan et al., 1980; Johnson and Robinson, 1988). Alcohol abuse causes a distal dying-back neuropathy (Novak and Victor, 1974). Therefore, the distal part of the long vagal fibres to the heart are affected before the shorter sympathetic fibres to splanchnic and other blood vessels. This has been confirmed pathologically. There is significant reduction in the density of myelinated fibres in the distal parts of the vagus and carotid sinus nerves, and relative sparing of the splanchnic nerves (Low et al., 1975a; Guo et al., 1987; Tamura et al., 1988). The pres-

A.J. McDougall, J.G. McL.eod/Joumal

ence of an autonomic neuropathy is associated with a worse prognosis (Johnson and Robinson, 1988). 3.4. Malignancy Localised abnormalities of sweating with hyperhidrosis and piloerection may result from direct irritation of nerves or nerve roots by malignancies (Walsh et al., 1976). Autonomic abnormalities may also occur as a paraneoplastic or ‘remote’ effect of cancer. The recognised syndromes that may occur are paraneoplastic dysautonomia (autonomic neuropathy), subacute sensory neuronopathy, enteric neuronopathy, and the Lambert-Eaton myasthenic syndrome (LEMS) (Khurana, 1993). Paraneoplastic dysautonomia (autonomic neuropathy) is characterised by autonomic dysfunction with no or minimal somatic neurological dysfunction. This condition most often occurs with small cell lung carcinoma, but is also reported with lymphomas and pancreatic adenocarcinoma (Thomas and Shields, 1970; Chiappa and Young, 1973; Van Lieshout et al., 1986). The autonomic symptoms are similar to those of acute dysautonomia (see above), and often precede the diagnosis of malignancy by several months. They are usually progressive, but improvement or resolution may follow successful treatment of the underlying malignancy (Park et al., 1972). Subclinical autonomic dysfunction may be very common in association with malignancies. Turner et al. (1993) found that 80% of patients presenting with Hodgkin’s disease and other lymphomas prior to chemotherapy had abnormal cardiovascular autonomic function tests. No patients in this study had symptomatic or clinical autonomic dysfunction. Subacute sensory neuronopathy comprises a primarily sensory neuropathy in association with cancer (DennyBrown, 1948). Pathological findings are neuronal loss and perivascular inflammatory infiltrates in dorsal root ganglia, with secondary axonal degeneration of sensory nerves, dorsal roots and posterior columns of the spinal cord. In some patients there is more widespread nervous system dysfunction including dementia, cerebellar degeneration, brainstem abnormalities, and myelopathy. It is strongly associated with small cell carcinoma of the lung and serum antineuronal nuclear antibodies (anti-Hu) (Graus et al., 1986; Anderson et al., 1988). A range of autonomic abnormalities from tonic pupils to generalised autonomic dysfunction may be present (Anderson et al., 1988). Enteric neuronopathy is seen with small cell lung carcinoma and, less commonly, with other malignancies. Symptoms of gastrointestinal pseudo-obstruction, such as progressive constipation, abdominal pain, and vomiting, usually precede diagnosis of the tumour (Chinn and Schuffler, 1988). Investigations show delayed gastric emptying and gastrointestinal dysmotility. Some patients have more widespread autonomic impairment. The pathological changes are a loss of myenteric plexus neurones, sec-

of rhe Neurological Sciences I38 (1996) 1-13

I

ondary axonal degeneration, and a lymphocytic inflammatory cell infiltrate (Lennon et al., 1991). Symptoms may improve following treatment of the malignancy (Sodhi et al., 1989). Autonomic dysfunction is present in about three-quarters of cases of LEMS (O’Neill et al., 1988). It is an acquired presynaptic disorder of neuromuscular transmission with a reduction in presynaptic quanta1 release of acetylcholine in the peripheral nervous system. Antibodies with specificity for neuronal presynaptic voltage sensitive calcium channels have been detected and are thought to be pathogenic (Roberts et al., 1985; Kim and Neher, 1988). This syndrome may be present in the absence of malignancy; tumour-associated cases occur most frequently with small cell carcinoma of the lung, but have also been reported with lymphoma and carcinoma of various organs. Autonomic abnormalities of cholinergic function predominate, but there are also sympathetic abnormalities. Findings include dry mouth, impaired lacrimation and sweating, impotence, constipation, and postural hypotension (Khurana et al., 1988). The autonomic abnormalities may resolve following successful tumour therapy (Mamdani et al., 198.5). In patients without tumours, immunosuppression with plasmapheresis, corticosteroids, and other medications have been used with variable success (Dau and Denys, 1981). Guanidine hydrochloride, 4-aminopyridine, and 3,4-diaminopyridine are used to enhance neuromuscular transmission and provide symptomatic relief (MCEVOY et al., 1989). These drugs reduce neuronal voltage-dependent potassium conductance producing prolonged depolarisation with increased voltage-dependent calcium influx which results in increased quanta1 release of acetylcholine. 3.5. Toxic neuropathies 3.5.1. Vincristine Peripheral neuropathy is one of the dose-limiting side effects of this medication (Casey et al., 1973). This drug disrupts microtubules and results in axonal degeneration (McLeod and Penny, 1969). Autonomic abnormalities, such as postural hypotension, constipation, paralytic ileus, and urinary retention, may appear early in the course of treatment and are not closely related to the development of a peripheral somatic neuropathy (Hancock and Naysmith, 1975; Lahtinen et al., 1989). 3.5.2. Cisplatin Dose-related neurotoxic side effects such as peripheral neuropathy, retrobulbar neuritis and ototoxicity are well recognised. An autonomic neuropathy with postural hypotension may be associated with these abnormalities (Rosenfeld and Broder, 1984). 3.5.3. Tax01 This antineoplastic drug disrupts microtubule assembly and causes a peripheral sensory neuropathy as one of its

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dose-limiting side effects. It may cause an autonomic neuropathy (Jerian et al., 1993). 3.5.4. Amiodarone A sensorimotor peripheral neuropathy occurs in about 10% of patients taking this drug (Palakurthy et al., 1987). Autonomic failure with postural hypotension has been reported (Manolis et al., 1987). 3.5.5. Perhexiline Perhexiline maleate may cause a peripheral neuropathy. Some patients may also develop an autonomic neuropathy with postural hypotension and an abnormal Valsalva ratio (Fraser et al., 1977). 3.5.6. HeaLly metals Thallium poisoning can cause tachycardia and hypertension in association with a peripheral neuropathy (Bank et al., 1972). In arsenic poisoning, excessive sweating and impairment of sweating over the extremities have been described (Le Quesne and McLeod, 1977). Subacute or chronic inorganic mercury poisoning in children can cause acrodynia or pink disease manifested by tachycardia, hypertension, pain and redness of the extremities and profuse sweating (Wakamy and Hubbard, 1948). 3.5.7. Organic solcents Industrial workers exposed to organic solvents, particularly carbon disulphide, have been found to have cardiovascular parasympathetic abnormalities as well as a peripheral sensorimotor neuropathy (Matikainen and Juntunen, 1985). Hexacarbon neuropathy may follow industrial exposure or inhalant abuse. Inhalation of n-hexane and methyl-nbutyl-ketone can cause a rapidly progressive polyneuropathy associated with autonomic features of excessive or impaired sweating, vasomotor alterations of the extremities, postural hypotension and impotence (Altenkirch et al., 1977). 3.5.8. Acrylamide Acrylamide is an industrial chemical; it is neurotoxic in the soluble monomeric form in which it is manufactured and distributed. The major toxic effect in humans is a predominantly sensory neuropathy, often preceded by blueness and excessive sweating of the extremities due to disturbed sympathetic function (Auld and Bedwell, 1967). This chemical has also been used to produce experimental autonomic neuropathies in laboratory animals (Post and McLeod, 1977). 3.5.9. Vacor Vacor (N-3-pyridylmethy-N-p-nitrophenylurea) is a rodenticide that antagonises nicotinamide metabolism. Accidental or deliberate suicidal ingestion results in acute hyperglycaemic ketoacidosis and an autonomic and so-

of the Neurological Sciences 138 (1996) l-13 matic peripheral neuropathy. Autonomic manifestations include postural hypotension and gastrointestinal hypomotility (Pont et al., 1979; LeWitt, 1980). 3.6. Chronic injlammatoty (CZDP)

demyelinating polyneuropathy

This condition causes only mild autonomic abnormalities. Ingall et al. (1990) studied 14 patients and found impaired sweating with the thermal sweat test in 5 patients and mild impairment of some cardiovascular parasympathetic tests in 3 patients. No patients had symptoms of autonomic dysfunction. There are only a few reports of symptomatic autonomic dysfunction in CIDP (Dyck et al., 1975; Prineas and McLeod, 1976). These findings are in contrast to the marked autonomic abnormalities that may occur with the Guillain-Barre syndrome. This may be due to the only minor involvement of unmyelinated nerve fibres in CIDP (Ingall et al., 1990). 3.7. Infections 3.7. I. Leprosy Leprosy is one of the most common causes of peripheral neuropathy and may be associated with autonomic dysfunction. Loss of sweating over the skin supplied by affected nerves is the most common autonomic abnormality; cardiac denervation, postural hypotension, widespread anhidrosis, and impaired autonomic function tests have also been described (Khattri et al., 1978; Radhakrishnan et al., 1978). Abnormalities of cardiovascular parasympathetic tests are more common and occur earlier in the illness than those of cardiovascular sympathetic tests. The severity of autonomic changes is related to the duration of leprosy (Ramachandran and Neelan, 1987). Abnormalities of fingertip vasomotor reflex tests, as measured by a laser Doppler flowmeter, may be an early indication of nerve damage (Beck et al., 1991). 3.7.2. Human immunodejiciency k-us (HIV) Autonomic dysfunction is a common complication of HIV infection. The most prominent symptoms are syncope, impotence, bladder and bowel dysfunction, and anhidrosis. Abnormalities of autonomic function tests may be found in the early stage of the illness, but are more common and more severe in patients with AIDS, with up to 80% of this group having abnormalities (Ruttimann et al., 1991; Welby et al., 1991). The mechanism of autonomic dysfunction in HIV infection is uncertain. It is associated with widespread changes in the central and peripheral nervous system and the abnormalities of autonomic tests do not correlate with the presence of a peripheral somatic neuropathy (Cohen and Laudenslager, 1989; Freeman and Cohen, 1993). The effects of antiretroviral therapy on HIV-associated autonomic dysfunction have not been systematically studied.

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3.7.3. Chagas’ disease Chagas’ disease (American trypanosomiasis) is caused by infection with the protozoan parasite Trypanosoma cruzi, and is widespread in Latin America with at least 20 million people being affected (Femandez et al., 1992). Autonomic nervous system abnormalities, particularly those affecting the gastrointestinal tract and heart, occur in the chronic phase of the infection. There is destruction of autonomic ganglia and enteric plexus neurones throughout the digestive tract. In the heart there are pathological changes in the myocardium and conducting system as well as in autonomic ganglia and postganglionic neurones. Multifocal inflammatory lesions associated with demyelination are found in the peripheral nervous system of experimental animals infected with this parasite (Said et al., 1985). The neuronal damage is thought to be due to a cell-mediated delayed-type hypersensitivity immune response (Femandez et al., 1992). Autonomic manifestations include prominent gastrointestinal motility dysfunction with dysphagia, achalasia, aperistalsis, megaoesophagus, constipation, intestinal volvulus, and megacolon. Cardiovascular autonomic changes include cardiac arrhythmias, sudden death, and postural hypotension. Autonomic function tests show widespread abnormalities of cardiovascular reflex control; ocular involvement with parasympathetic denervation of the iris also occurs (Iosa et al., 1990; Idiaquez, 1992b). A clinical trial of mixed ganglioside therapy has shown improvement in cardiovascular autonomic reflex function (Iosa et al., 1991). 3.7.4. Diphtheria Diphtheria results in a demyelinating motor polyneuropathy in about 20% of cases. The presence of parasympathetic cardiovascular reflex dysfunction may explain how tachycardia can occur in the absence of myocarditis in some cases (Solders et al., 1989; Idiaquez, 1992a). The severity of parasympathetic abnormalities may not be closely related to the severity of peripheral motor nerve damage. Sympathetic abnormalities have not been found.

of the Neurological Sciences 138 (1996) l-13

3.9. Inflammatory bowel disease Abnormalities of cardiovascular autonomic function tests have been found in a large proportion of patients with Crohn’s disease and ulcerative colitis. The autonomic abnormalities did not correlate with the severity, duration, or treatment of the bowel disease, or the presence of a peripheral somatic neuropathy (Lindgren et al., 1991, 1993). 3.10. Chronic lung disease Patients with hypoxaemic chronic obstructive pulmonary disease have subclinical abnormalities in parasympathetic cardiovascular autonomic function tests and tests of sudomotor function; sympathetic cardiovascular autonomic function tests are spared (Stewart et al., 1991; Stewart et al., 1994). It has been proposed that intraneural hypoxia may be the pathogenic mechanism for these changes. 3. Il. Multiple symmetric lipomatosis (Madelung ‘s disease) The characteristic feature of this condition is the formation of large symmetric subcutaneous fat masses and the deep accumulation of adipose tissue, associated with metabolic abnormalities of adipose tissue. A peripheral sensorimotor neuropathy of variable severity is part of this condition. Autonomic symptoms include gustatory sweating, hyperhidrosis of the feet, impotence, and resting tachycardia. Abnormal cardiovascular autonomic function tests are found in most affected patients (Enzi, 1984; Enzi et al., 1986). There is evidence that this disease may be due to mitochondrial dysfunction (Klopstock et al., 19941. Acknowledgements A.J.M. was supported by an NHMRC Medical Postgraduate Research Scholarship and a National Multiple Sclerosis Society of Australia Project Grant.

3.8. Connectice tissue diseases Abnormalities of autonomic function tests have been found in a number of connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, and Sjiigren’s syndrome. In most cases, these changes have been asymptomatic (Edmonds et al., 1979; McCombe et al., 1987; Klimiuk et al., 1988; Liote and Osterland, 1994). There are case reports of acute autonomic neuropathy (acute dysautonomia) with severe autonomic failure occurring in association with systemic lupus erythematosus. These cases responded to treatment with corticosteroids (Hoyle et al., 1985; Arruda et al., 1989). Severe autonomic neuropathy in amyloidosis secondary to rheumatoid arthritis has been reported (McGill et al., 1986).

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