Peripheral nerve disorders continued - Generalized neuropathies.
Essentials
Generalized neuropathies—causes include (1) diabetes mellitus—most commonly producing a symmetrical sensory polyneuropathy; autonomic neuropathy may be debilitating; (2) alcohol—usually in association with thiamine deficiency (3) other metabolic/endocrine disorders—e.g. amyloidosis, uraemia, myxoedema, acromegaly, critical illness polyneuropathy; (4) toxic—including industrial/environmental (e.g. acrylamide, lead, thallium) and dr (e.g. cisplatin, isoniazid, vincristine, thalidomide) substances; (5) deficiencies—e.g. thiamine, vitamin B12; (6) inflammatory—e.g. Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, paraprotein associated neuropathy; (7) infection related—leprosy Lyme borreliosis, HIV-1 infection; (8) granulomatous—sarcoidosis; (9) vasculitic disorders; (10) neoplastic and paraneoplastic—most often with bronchial or ovarian malignancy; (11) genetic conditions—e.g. porphyria, familial amyloid polyneuropathy, Charcot–Marie–Tooth (hereditary motor and sensory neuropathy) disease, hereditary neuropathy with liability to pressure palsies, Refsum’s disease; and (12) chronic idiopathic axonal polyneuropathy—the cause of about 25% of cases of late onset symmetrical polyneuropathy remains unknown despite extensive investigation.
Generalized neuropathies
Neuropathies related to metabolic and endocrine disorders
Diabetes mellitus
A significant degree of peripheral neuropathy develops in about 15% of patients with diabetes, although a substantially greater number have either minor symptoms without signs or evidence of a subclinical neuropathy on clinical examination or based on abnormalities of nerve conduction. In general, the neuropathies that appear can be divided into symmetrical sensory and autonomic polyneuropathies, on the one hand, and isolated peripheral nerve lesions or multifocal neuropathies, on the other. Mixed syndromes are common.
The most common form is a symmetrical sensory polyneuropathy, giving rise to numbness and tingling paraesthesiae in the toes and feet, and less often in the fingers. Aching or lancinating pains in the feet and legs, particularly at night, may be a troublesome feature. Examination reveals loss of vibration sense in the feet, depression of the ankle jerks, and distal cutaneous sensory impairment. Neuropathic plantar ulcers, and occasionally Charcot’s joints, are an important complication. Loss of the sense of pain results in perforating ulcers on the feet and neuropathic joint degeneration, particularly in the toes and tarsal joints; impaired postural sense may give rise to an ataxic gait. An acute painful diabetic neuropathy also occurs which predominantly affects the lower limbs. The onset is often associated with poor diabetic control and precipitate weight loss (‘diabetic neuropathic cachexia’). Some patients have a pure small fibre neuropathy with pain, reduced temperature, and pinprick sensation, but normal reflexes and preserved vibration, and light touch and position sensation.
Autonomic neuropathy frequently accompanies the sensory neuropathy and may be the salient manifestation, and rarely occurs in isolation. Pupillary disturbances usually take the form of a reduced response to light. Gustatory facial sweating provoked by the smell and taste of food can be troublesome. Anhidrosis may occur distally in the limbs; if it is extensive and also affects the trunk, heat intolerance can result. Symptoms referable to the alimentary tract include dysphagia from oesophageal involvement, episodes of vomiting related to gastric atony (gastroparesis), and episodic nocturnal diarrhoea, often alternating with periods of constipation. Those related to the genitourinary system include erectile dysfunction, retrograde ejaculation, bladder atony with difficulty in voiding, and urinary retention with overflow. Vascular denervation sometimes results in orthostatic hypotension, and cardiac denervation may be demonstrable by an elevated resting heart rate and the absence of beat-to-beat variation with respiration. The risk and progression of diabetic polyneuropathy are reduced by strict glycaemic control.
Isolated nerve lesions tend to occur more commonly in older people with diabetes. At times they develop insidiously, but at other times they have an abrupt onset with pain. Of the cranial nerves, the nerves to the external ocular muscles, particularly the third and sixth, and also the facial nerve, are affected most often. In contradistinction to the effects of compression of the third nerve by a carotid aneurysm, pupillary innervation is often spared. On the trunk, isolated root lesions may occur. In the limbs, the lesions tend to occur at the common sites of compression or entrapment. It seems likely that the nerves of people with diabetes exhibit an excessive vulnerability to damage from pressure.
Diabetic amyotrophy (also known as diabetic lumbosacral radiculoplexus neuropathy or proximal diabetic neuropathy) represents a particular example of a multifocal neuropathy that develops usually in older obese individuals with diabetes. It consists of an asymmetrical proximal motor syndrome that affects the anterior thigh muscles and hip flexors, and sometimes also the anterolateral muscles of the lower leg. Less commonly it is symmetrical. Its onset may be acute or insidious and is often accompanied by pain, particularly at night. There is generally little or no associated sensory loss. The knee jerks are usually depressed or absent. Inflammatory lesions including vasculitis have been demonstrated in peripheral nerves in proximal diabetic neuropathy, leading to trials of immunomodulatory therapy, which have not been conclusive.
The causation of diabetic neuropathy is uncertain. It tends to occur more often in people with poorly controlled diabetes, but the correlation is not close. In type 2 diabetes it may be the presenting symptom or occur for the first time on initiation of treatment with insulin. There is evidence to suggest that diabetic microangiopathy is important in the genesis of isolated nerve lesions. Metabolic factors are probably more important in the origin of the symmetrical polyneuropathies, but their nature is uncertain. An increased concentration of sorbitol in nerves secondary to hyperglycaemia may be involved in causing nerve fibre dysfunction. People with diabetes are more at risk of developing some other neuropathies including entrapment neuropathies and chemotherapy-induced neuropathy. Patients with impaired glucose tolerance or impaired fasting glycaemia also have an increased risk of neuropathy, even if they do not have diabetes.
Focal peripheral nerve lesions and diabetic amyotrophy, if of acute onset, may recover adequately, as does acute painful diabetic neuropathy when satisfactory glycaemic control is achieved. Symmetrical sensory and autonomic neuropathy, once established, recovers less satisfactorily, even with good diabetic control. Correcting the hyperglycaemia by continuous subcutaneous insulin infusion or transplantation of the pancreas stabilizes the neuropathy. Trials of aldose reductase inhibitors to reduce sorbitol accumulation have not given clear evidence of improvement in neuropathy.
Care of the feet is vitally important in diabetic sensory neuropathy, to prevent the development of chronic ulceration. Pain may be helped by tricyclic antidepressants, duloxetine, antiepileptic drugs, especially pregabalin, gabapentin, or carbamazepine, or tramadol. Hypotension can be improved by raising the head of the bed at night, high fluid and salt intake, and compression stockings. More severe cases may require treatment with the α-agonist midodrine and fludrocortisone. Gastroparesis may respond to metoclopramide, domperidone, or erythromycin. In extreme cases, persistent vomiting may necessitate a roux-en-Y gastroenterostomy. Diabetic diarrhoea can be helped by low-dose tetracycline or diphenoxylate, loperamide, or codeine phosphate. An atonic bladder can be managed in the earlier stages by regular voiding, lower abdominal compression, and straining. More severe cases should undergo urodynamic studies and are usually best managed by intermittent self-catheterisation. Urinary tract infections should be treated promptly. Bladder neck resection can be useful in carefully selected cases. Erectile dysfunction may be treated with one of the phosphodiesterase inhibitors, sildenafil, tadalafil, or vardenafil, and in the UK their use is funded by the NHS for diabetic neuropathy. If such treatment fails, referral to a specialist clinic should be made and intrapenile injections of alprostadil (prostaglandin E1) may be considered.
Amyloidosis
The various forms of amyloid disease are described here: Amyloidosis. The peripheral nerves may be involved in primary amyloidosis due to plasma cell dyscrasia and in amyloidosis related to myeloma (light chain amyloidosis). There are also several dominantly inherited forms of amyloid neuropathy, the most important of which are the result of mutations in the gene for transthyretin (TTR), including the Portuguese type (see later). Isolated lesions may occur from the infiltration of amyloid into nerves or from compression of the median nerve in the carpal tunnel because of deposits in the flexor retinaculum. More strikingly, a generalized neuropathy may develop. It begins with selective loss of pain and temperature sensation in the feet, and later in the hands. Motor involvement, loss of tendon reflexes, and impairment of other sensory modalities occur later. Autonomic involvement is an early feature, causing impotence, orthostatic hypotension, bladder atony, and disturbances of alimentary function. Amyloid deposits are present in the peripheral nerve trunks, which may be enlarged, and in the dorsal root and sympathetic ganglia.
No treatment influences the progress of the neuropathy apart from liver transplantation in neuropathy due to TTR mutations. The use of stem cell transplantation is being explored in amyloidosis related to malignant plasma cell dyscrasias. The spontaneous pains are sometimes improved by antiepileptic (pregabalin, gabapentin, or carbamazepine) or tricyclic antidepressant drugs. Care must be taken to prevent damage to the anaesthetized feet, lower legs, and hands. Autonomic symptoms may require treatment as described for diabetic neuropathy.
Carpal tunnel syndrome is frequent in patients on long-term haemodialysis, related to deposition of amyloid in the flexor retinaculum derived from retained β2-microglobulin.
Uraemia
Uraemic neuropathy did not become a clinical problem until the advent of treatment of end-stage renal failure by haemodialysis. It occurs in patients with severe chronic renal failure. It was most often seen in patients undergoing treatment with periodic haemodialysis but is now much less frequently a problem. The symptoms are usually predominantly sensory, with numbness and tingling paraesthesiae, and burning in the feet. Restless legs syndrome and cramps are often conspicuous. A distal motor neuropathy may be associated and occasional cases are purely motor. The condition is not necessarily improved by increased haemodialysis but does improve after kidney transplantation. Failure to clear ‘middle molecules’ that are toxic to axons has been proposed but not proved to be the mechanism. The nerve trunks in the arm and forearm are at risk during surgery for placing arteriovenous anastomoses for dialysis. Symptoms may be produced by surgical damage, ischaemia, sometimes partly attributable to shunting, and compression.
Myxoedema
Compression of the median nerve in the carpal tunnel in myxoedema has already been discussed. Rarely a generalized mixed motor and sensory neuropathy develops. This improves on treatment of the hypothyroidism. The slow contraction and relaxation observed in the tendon reflexes is due not to a disturbance of peripheral nerve function, but to an alteration in the contractile mechanism of the muscle fibres.
Acromegaly
In addition to carpal tunnel syndrome, acromegaly may cause a sensory and motor polyneuropathy. This may occur independently of diabetes mellitus and the peripheral nerves are thickened because of an overgrowth of endoneurial and perineurial connective tissue. A similar neuropathy is occasionally observed in pituitary gigantism.
Critical illness polyneuropathy
A generalized polyneuropathy involving widespread axonal degeneration may be encountered in patients in intensive care units with sepsis and multiple-organ failure. The neuropathy is discovered when attempts are made to wean the patient from the ventilator and is difficult to distinguish from critical illness myopathy. Both may occur together. The precise cause of critical illness polyneuropathy is unknown. It is particularly likely to occur after the use of prolonged neuromuscular junction blockade and high-dose corticosteroids. Despite the development of severe wasting and weakness, satisfactory recovery may occur if the critical illness itself can be cured.
Other metabolic disorders
Symmetrical sensory and autonomic polyneuropathy probably does occur with cirrhosis but most cases are the result of the alcoholism that is its most common cause. A mild, painful, sensory neuropathy is occasionally encountered in primary biliary cirrhosis, sometimes related to xanthomatous deposits in the cutaneous nerve trunks. A motor neuropathy, especially affecting the hands, is a rare consequence of severe recurrent hypoglycaemia due to an insulinoma.
Toxic neuropathies
Industrial, environmental, and pharmaceutical substances
Acrylamide
Acrylamide monomer was formerly a cause of peripheral neuropathy because it was absorbed through the skin by workers manufacturing the nontoxic polymers used in waterproofing and other industries. It caused a distal sensory and motor neuropathy with prominent numbness and disequilibrium. Distal axonal degeneration occurred and slow improvement followed cessation of exposure. With proper safety precautions this neuropathy should not occur.
Arsenic
Arsenical poisoning is occasionally seen as a result of accidental or homicidal ingestion of insecticides containing arsenic, or from indigenous medicines in India. Gastrointestinal symptoms develop after acute ingestion, followed by a mixed sensory and motor neuropathy after 1 to 3 weeks. Desquamation of the skin of the feet and hands takes place after about 6 weeks, and white lines (Mees’ lines) appear in the nails. With ingestion of smaller quantities on a chronic basis, gastrointestinal symptoms are less obtrusive and a slowly progressive neuropathy makes its appearance. The skin may become generally pigmented or show focal ‘raindrop’ pigmentation, and hyperkeratosis of the palms of the hands and soles of the feet may appear. Slow recovery from the neuropathy occurs with removal from exposure. Chelating agents are of value in treating the non-neurological complications, but it is uncertain whether they are effective for the neuropathy.
Lead
Lead neuropathy is now rare in the United Kingdom, although it was encountered as a consequence of the contamination of drinking water by lead pipes in old buildings. Subclinical neuropathy may be detectable in lead workers. It remains a hazard in certain parts of the world from the use of lead glazes in pottery. Lead poisoning usually causes a triad of abdominal pain with constipation, anaemia, and neuropathy. The neuropathy is predominantly motor and affects the upper much more than the lower limbs. It is frequently asymmetrical and typically produces weakness of first the finger and then the wrist extensors. The ‘lead colic’ that may occur is probably a manifestation of autonomic involvement. Severe chronic lead poisoning causes bluish discoloration of the gums just below the teeth, especially if they are carious. The neuropathy improves on cessation of lead intake. Chelating agents accelerate removal of lead but it is uncertain which of dimercaprol, edetate, penicillamine, and 2,3-dimercaptosuccinic acid (DMSA) is the best.
Mercury
Exposure to inorganic mercury salts and organic mercurial compounds may lead to neurological damage. There was as an outbreak of poisoning in Minamata Bay related to the consumption of fish contaminated by organic mercury. Dementia, cortical blindness, and ataxia occur, together with paraesthesiae, the last due perhaps to involvement of the dorsal root ganglia. Peripheral neuropathy was also a component of ‘pink disease’ in infants, consisting of anaemia, light sensitivity, skin rash, weight loss, and hypotonia. It was caused by the inorganic mercury in teething powders.
Thallium
This is present in certain pesticides and rodent poisons, and was formerly used as a depilatory agent. Accidental or homicidal poisoning is occasionally encountered. Acute ingestion causes nausea, vomiting, and diarrhoea. In severe cases coma develops rapidly. In milder cases there are central nervous symptoms including anxiety and choreoathetosis, and the development of a progressive, very painful, sensory and motor neuropathy. Alopecia develops later, after about 2 or 3 weeks, and renal damage may occur. Both Prussian blue to bind thallium in the gut and chelating agents to clear thallium from the body have been used as treatment.
Organophosphates
Organophospates, especially tri-ortho-cresylphosphate, have been widely used as lubricants and insecticides. The original description of organophosphate poisoning was in relation to illegal liquor distillation in the United States of America during the prohibition era (ginger jake paralysis). A large outbreak occurred in Morocco from contaminated cooking oil. Accidental or suicidal acute poisoning with high doses causes an acute muscarinic syndrome with diarrhoea, sweating, salivation, and meiosis. After 12 hours to 4 days patients develop generalized weakness, possibly due to neuromuscular blockade, confusion, and even coma. Recovery from this begins after 1 or 2 weeks. However, between 1 and 3 weeks after the acute exposure, some patients develop a subacute predominantly motor neuropathy—‘organophosphate-induced delayed peripheral neuropathy’. Recovery is slow and often incomplete. Claims that chronic, very-low-dose exposure to the organophosphates in agricultural insecticides causes peripheral neuropathy have not been proven.
Other industrial substances
Carbon disulphide, used in the manufacture of rayon, occasionally gives rise to a mild sensory neuropathy. Neuropathy may occur as a result of industrial exposure to the organic solvents n-hexane and methyl-n-butyl ketone. The former is also encountered as a consequence of solvent abuse; n-hexane, which has an intoxicant action, has been used as a solvent in certain glues. Other industrial agents causing neuropathy are ethylene oxide and methyl bromide. Trichlorethylene (or an impurity) has caused trigeminal neuropathy.
Iatrogenic
Bortezomib
Various different neuropathies have been described with the proteosome inhibitor bortezomib, an antineoplastic agent used for multiple myeloma. These include a painful subacute sensory axonal neuropathy and a more acute sensory and motor neuropathy that can resemble Guillain–Barré syndrome.
Isoniazid
A mixed motor and sensory neuropathy may be produced by isoniazid and is more likely to occur in individuals who acetylate the drug slowly. The neuropathy is related to interference with pyridoxine metabolism. Axonal degeneration occurs in the peripheral nerves. The neuropathy recovers slowly when the patient stops taking the drug; this may be prevented by giving pyridoxine, which does not interfere with the antituberculous action of the isoniazid.
Nitrofurantoin
Excessively high blood levels of nitofurantoin as may occur in patients with reduced renal function, can cause a rapid-onset mixed motor and sensory neuropathy, which may be confused with Guillain–Barré syndrome.
Nucleoside analogue reverse transcriptase inhibitors
The nucleoside analogue reverse transcriptase inhibitors (zalcitabine, didanosine, and stavudine) all cause a dose-dependent, subacute, painful, sensory axonal neuropathy. The neuropathy continues to progress for some weeks after the patient stops taking the drug but this eventually improves. It may be difficult to distinguish from the painful neuropathy caused by HIV itself and withdrawal of the drug is usually necessary to make the distinction.
Phenytoin
After taking phenytoin for a prolonged period, patients may report symptoms of a mild sensory neuropathy. More commonly the neuropathy is asymptomatic but detectable on clinical and especially neurophysiological examination. Platinum Both cisplatin and carboplatin may cause a predominantly sensory neuropathy after taking several courses. Recovery from the neuropathy is often poor. Ototoxicity is more frequent, causing high-tone deafness and tinnitus.
Pyridoxine
Pyridoxine, if taken in large doses as ‘megavitamin therapy’, causes a severe sensory neuropathy with numbness of the feet and an unsteady gait. It is disputed whether chronic doses as low as 100 mg daily cause neuropathy, the daily requirement being only 2 mg.
Taxanes
The taxanes, paclitaxel and docetaxel, used in the treatment of neoplasia, cause a dose-dependent, predominantly sensory axonal neuropathy. It presents with numbness and paraesthesiae in the feet and worsens with each dose. With high doses weakness develops. If the drug is stopped the neuropathy worsens for some weeks before improving, a phenomenon called ‘coasting’.
Thalidomide
Thalidomide, which has found a niche in the treatment of some vasculitides and multiple myeloma, also causes a dose-dependent, predominantly sensory neuropathy. It presents with painful paraesthesiae and cramps in the legs. It may be associated with palmar erythema, brittle nails, and tremor. It improves if the drug is stopped.
Vincristine
Vincristine produces a dose-dependent axonal neuropathy, and its therapeutic use in neoplasia is limited by this side effect. Patients first develop distal paraesthesiae and lose their ankle reflexes. If the drug is continued, they gradually develop distal sensory loss and may eventually develop weakness that comes on quite rapidly. The neuropathy improves satisfactorily if the drug is withdrawn.
Other substances
Other drugs that may give rise to neuropathy are doxorubicin, amiodarone, chloroquine (with myopathy), dapsone, disulfiram, ethambutol, gold, metronidazole, misonidazole, nitrous oxide (with a myelopathy), podophyllin, suramin, and zimeldine. This list is not exhaustive and if a patient with an unexplained neuropathy is taking drugs of any sort, it is worth checking whether any of the drugs is reported to cause neuropathy.
Deficiency neuropathies
Coeliac disease
There is an association between coeliac disease and some neurological syndromes including cerebellar ataxia and peripheral neuropathy. In patients with malnutrition or vitamin deficiency, this is easily explained. Most patients with neurological manifestations experience preceding gastrointestinal symptoms before developing peripheral neuropathy. Nevertheless some patients do develop a peripheral neuropathy, usually a symmetrical, distal, sensory axonal neuropathy, in their absence. This now justifies at least screening for antibodies associated with coeliac disease in patients with otherwise unexplained axonal neuropathy. Whether the associated neuropathy is caused by subtle nutritional deficiency or an unidentified toxic factor is not known. Regardless of this, improvement after institution of a gluten-free diet has been reported.
Thiamine deficiency
Thiamine deficiency is the cause of dry beri-beri which occurs in severely malnourished communities, especially those subsisting on diets largely made up of polished rice, and medical conditions that reduce thiamine intake, most commonly chronic alcohol abuse, and after gastric surgery. Initial symptoms of fatigue, irritability, and cramps are followed by the development of painful numbness in the feet. In severe cases, involvement of the recurrent laryngeal nerves may lead to hoarseness of the voice. The neuropathy may be associated with a cardiomyopathy (‘wet beri-beri’). The diagnosis may be supported by a reduced activity of erythrocyte transketolase. This enzyme requires thiamine as a cofactor. Distal axonal degeneration occurs in the peripheral nerves and slow recovery ensues with vitamin replacement.
Strachan’s syndrome
Strachan’s syndrome, originally described in Jamaica but also observed in other parts of the world under conditions of nutritional deprivation, is characterized by the combination of a painful sensory neuropathy, optic neuropathy, and deafness, in association with orogenital dermatitis. There may also be features of a myelopathy. It is assumed to be due to deficiency of the B vitamins, but the precise deficit has not been identified. It improves with B vitamin and folate supplementation.
Alcoholic neuropathy
This usually occurs on a background of nutritional deficiency. The dietary intake of the person with alcohol problems is high in carbohydrates and low in vitamins. Moreover, such individuals are known to have a reduced capacity to absorb thiamine. A direct toxic effect of alcohol on peripheral nerves may also be involved. The clinical features of alcoholic neuropathy are similar to those of thiamine deficiency. Other deficiency states may coexist, such as the Wernicke–Korsakoff syndrome. Improvement may take place with vitamin replacement and reduced alcohol intake, but it is beset with the usual difficulties met in treating patients with alcohol problems.
Pyridoxine deficiency
As well as high doses of pyridoxine causing neuropathy, as described above, pyridoxine deficiency may contribute to the neuropathy that occurs in nutritional deficiency states. Isoniazid neuropathy is related to an interference with pyridoxine metabolism.
Vitamin E deficiency
Vitamin E deficiency occurs in some hereditary disorders and in hepatobiliary and bowel disorders that impair its absorption. It produces a multisystem neurological disorder in which cerebellar ataxia is the most prominent problem but peripheral neuropathy also occurs. It may be diagnosed by measuring plasma concentrations of α-tocopherol, the most active form of vitamin E.
Vitamin B12 deficiency
Vitamin B12 deficiency, from whatever cause, may be responsible for the development of a distal sensory neuropathy, with ‘glove-and-stocking’ sensory loss and paraesthesiae, and areflexia, either in isolation or in association with a myelopathy or other central nervous system manifestations. Haematological changes are not always present. The peripheral neuropathy improves more satisfactorily with treatment than the central disturbances. A peripheral neuropathy is one component of Nigerian ataxic neuropathy, in which the other features are posterior column degeneration, sensorineural deafness, and optic atrophy. It has been suggested that an interference with vitamin B12 metabolism by cyanide derived from cassava in the diet, combined with nutritional deficiency, is responsible.
Inflammatory and postinfective neuropathies
Leprosy
Peripheral nerve involvement in leprosy is considered here: Leprosy (Hansen's disease)
Guillain–Barré syndrome
Guillain–Barré syndrome is the most common cause of acute neuromuscular paralysis in developed countries. Its annual incidence is between 1 and 2 per 100 000 throughout the world, being more common in men and older people. It consists of weakness of two or more limbs developing over a few days, with extremes of a few hours to up to 4 weeks. The tendon reflexes are lost. The illness often but not necessarily causes paraesthesiae, pain, and sensory loss. There are no signs of central nervous involvement. In two-thirds of cases there has been an infective illness between 1 and 6 weeks, most commonly 1 or 2 weeks earlier. The infection is most commonly an uncharacterized upper respiratory tract infection but alternatively gastroenteritis. About 25% of cases are due to preceding Campylobacter jejuni infection, but 15% result from a preceding cytomegalovirus infection, 5 to 10% from Epstein–Barr virus, and 1 to 5% from mycoplasma. Many other associated infections have been reported but not proved by large-scale epidemiological studies.
The onset is usually with the simultaneous development of weakness of the limbs, paraesthesiae, and numbness. Pain, including pain in the back, may be a prominent and confusing feature, especially in children. Weakness may be proximal, distal, or generalized in distribution, but is usually fairly symmetrical. The facial and bulbar muscles are commonly involved and sometimes the ocular muscles. About 25% of patients develop such severe respiratory muscle weakness for which they need intubation and artificial ventilation. Rarely a complete ‘locked-in’ state may develop. Autonomic disturbances include tachycardia, hypertension, and then later postural hypotension, bladder atony, and ileus. Papilloedema sometimes develops, possibly related to impaired resorption of cerebrospinal fluid as a result of the elevated protein content.
This same clinical picture may be caused by any of three pathological entities. In Europe and North America, AIDP is the underlying pathology in more than 90% of cases. Its pathogenesis is unclear but the hypothesis that it is due to a T-cell-mediated autoimmune response to one of several peripheral nerve myelin proteins is giving way to the idea that it is caused by a complement-fixing antibody directed against an unidentified ganglioside or combination of gangliosides. In China, Japan, and Mexico most cases are caused by acute motor axonal neuropathy. In such cases preceding Campylobacter jejuni infection is common and antibodies to the ganglioside GM1, GD1a, or both are usually present in the serum. Epitopes resembling the terminal sugars are present in the bacterial walls of the Campylobacter jejuni strains, which induce acute motor axonal neuropathy. The antibodies probably produce the neuropathy by reacting with gangliosides on the axolemma or at the motor nerve terminals, then blocking nerve conduction or inducing axonal degeneration. There is also a less common axonal motor and sensory neuropathy.
In AIDP, nerve conduction studies reveal evidence of motor nerve conduction block, slowing of motor nerve conduction, often multifocal, and reduced sensory nerve action potential amplitudes. In the axonal forms of the disease, the changes are those of an axonal neuropathy. During the first week, routine neurophysiological tests may be normal. Accurate identification of the neurophysiological type may require serial studies. The cerebrospinal fluid usually has an increased protein concentration, often markedly increased, and normal but sometimes slightly increased cell count (rarely more than 10 and by definition not more than 50/µl). The cells are lymphocytes and do not include neutrophils. There is no diagnostic test but antibodies to gangliosides, especially GM1, may be present, most commonly in the axonal forms of the disease. Diagnosis is therefore largely clinical, supported by the neurophysiological and cerebrospinal fluid findings. The differential diagnoses are acute muscle dysfunction (including hypo- or hyperkalaemia), neuromuscular junction disorders, other causes of neuropathy (including drugs, toxins, porphyria, and vasculitis), and cauda equina, cord, and brain-stem causes of paralysis.
The prognosis is very variable. About a quarter have a benign course, never losing the ability to walk. About a quarter require artificial ventilation, accounting for most of the 5% who die, and 20% are left with persistent disability so severe that they need help walking. Of the remainder, most are able to walk with help by 1 month and without aid by 3 months, and return to work or their usual activities by 6 months. Some patients have persistent fatigue.
The mainstays of treatment are careful monitoring for the development of respiratory failure and cardiac arrhythmia, prophylactic enoxaparin for bed-bound adult patients and excellent intensive care. Plasma exchange and intravenous immunoglobulin have both been shown to improve the rate and extent of recovery if given within the first 2, and perhaps 4 weeks. Controlled trials of treatment with corticosteroids have shown no beneficial effects. Pain may be a significant problem and require nonsteroidal anti-inflammatory drugs, amitriptyline, or pregabalin, and in severe cases opiates. Careful positioning and physiotherapy are important to avoid pressure sores and contractures. Exercise programmes are probably useful for fatigue.
Fisher’s syndrome
A syndrome of ophthalmoplegia, ataxia, and loss of the tendon reflexes was described by Miller Fisher in 1956 and is often called the Miller Fisher syndrome or more correctly Fisher’s syndrome. Similar to Guillain–Barré syndrome, it commonly follows an infection, progresses for a few days, and then plateaus and eventually improves. As in Guillain–Barré syndrome, the cerebrospinal fluid protein concentration is usually increased. Facial and bulbar palsies also occur and are accepted as part of the syndrome, but patients with associated limb weakness are regarded as having an overlap with Guillain–Barré syndrome. In the pure cases, motor nerve conduction remains normal but sensory action potentials disappear. The prognosis is excellent even without immunotherapy. The diagnosis is usually straightforward, but confusion with botulism and diphtheritic neuropathy may arise. In most patients with Fisher’s syndrome, antibodies to ganglioside GQ1b are present in the serum and are probably important in causing terminal nerve damage. Formes frustes of Fisher’s syndrome, with only some of the features, are sometimes encountered.
The features of ophthalmoplegia, ataxia, and, paradoxically, loss of the tendon reflexes may occur with another relatively benign condition, Bickerstaff’s brain-stem encephalitis. Signs of central nervous system involvement, including altered consciousness and extensor plantar responses, are also present. In addition there may be an increased cerebrospinal fluid cell count and abnormalities in the brain stem may be visible on MRI. Antibodies to ganglioside GQ1b may also be present in the serum of patients with Bickerstaff’s encephalitis.
Chronic inflammatory demyelinating polyradiculoneuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing disorder with weakness and sensory changes in the limbs developing over more than 8 weeks. Patients whose symptoms develop in less than 4 weeks are regarded as having the AIDP form of Guillain–Barré syndrome, whereas those whose symptoms progress over 4 to 8 weeks are considered to have subacute inflammatory demyelinating polyradiculoneuropathy. The three disorders probably constitute a spectrum. CIDP has emerged as an important treatable form of chronic neuropathy which has to be distinguished from the many less treatable causes of chronic axonal neuropathy. Electrophysiological tests are key to making the distinction. The hallmarks of CIDP are multifocal slowing of motor nerve conduction, often with partial conduction blocks, and prolonged duration of compound muscle action potentials. Sensory nerve action potentials are often reduced or absent. In typical cases, the clinical features are symmetrical but about 10% of patients have a multifocal disorder called the Lewis–Sumner syndrome or multifocal acquired demyelinating sensory and motor neuropathy.
Most patients with CIDP respond to treatment with corticosteroids, intravenous immunoglobulin, or plasma exchange. Prolonged treatment is necessary; it is hazardous with corticosteroids, expensive with intravenous immunoglobulin, and inconvenient with plasma exchange. Cytotoxic drugs, such as azathioprine, methotrexate, and ciclosporin, are often used and have appeared helpful in refractory cases but their efficacy has not been proved with randomized trials and controversy exists about which to choose.
Multifocal motor neuropathy
Multifocal motor neuropathy is a pure motor syndrome of weakness and wasting predominantly in the upper limbs, probably caused by antibodies to ganglioside GM1. The diagnosis depends on identifying multiple regions of motor nerve conduction block with preserved sensory nerve conduction through the same nerve segment. Most patients respond to intravenous immunoglobulin but this needs to be repeated approximately every month. Immunosuppressive drugs are often tried in severe cases but have not been proved to work in trials. Multifocal motor neuropathy may be worsened by corticosteroids.
Paraprotein-associated neuropathy
Malignant plasma cell dyscrasias may affect the peripheral nervous system. Multiple myeloma deposits may compress spinal nerve roots, causing pain and radicular symptoms as well as cord compression. Multiple myeloma is very rarely associated with an axonal neuropathy, possibly as a paraneoplastic manifestation. AL amyloidosis may cause peripheral nerve as well as other tissue infiltration and a severe neuropathy. Waldenström’s macroglobulinaemia may be associated with an axonal or demyelinating neuropathy, which resembles the syndrome of IgM monoclonal gammopathy of undetermined significance (MGUS) and antibodies to myelin-associated glycoprotein described below.
The mixed cryoglobulins in essential cryoglobulinaemia, sometimes associated with hepatitis C infection, cause a multiple mononeuropathy which is thought to be due the fact that cryoglobulins are circulating immune complexes. The treatment is that of the underlying condition.
Osteosclerotic myeloma and solitary plasmacytomas may both be associated with a paraneoplastic demyelinating neuropathy the pathogenesis of which is unclear. Removal of the neoplasm is often curative. By contrast the POEMS syndrome (polyneuropathy, organomegaly, oedema, M protein, and skin changes) is much more difficult to treat. This multisystem disorder is associated with very high concentrations of vascular endothelial growth factor in the plasma. Polyneuropathy is a required feature for the diagnosis and is usually a mixed axonal and demyelinating neuropathy. Papilloedema, peripheral oedema, skin pigmentation, and endocrinopathy may occur. It does not respond to corticosteroids or conventional immunotherapy but, if there is a localised sclerotic myeloma, it may respond to irradiation. Otherwise good results have been reported from peripheral blood stem cell transplantation and thalidomide-like drugs.
The most common association between peripheral neuropathy and a paraprotein is the coincidence with MGUS. Both peripheral neuropathy and MGUS become more common with advancing age, so the association is not necessarily causative. This is particularly true of paraproteins and axonal neuropathy. If there is no evidence of amyloid or a malignant plasma cell dyscrasia, an association between a paraprotein and an axonal neuropathy is probably coincidental because relevant autoantibody properties of the paraprotein have very rarely been described. The association between IgG and IgA MGUS and demyelinating neuropathy may also be coincidental, because these patients, and some of those with IgM MGUS, behave in every respect like patients with CIDP who have no paraprotein. It is always essential to look for evidence of an underlying plasma cell dyscrasia, which might be a solitary myeloma or plasmacytoma and may be difficult to find.
In patients with an IgM MGUS and demyelinating neuropathy, a search should be made for antibodies to myelin-associated glycoprotein because there is a not uncommon syndrome in which these are present. The characteristic features are of a very slowly progressive sensory, then sensory and motor demyelinating neuropathy, often with a postural tremor. Nerve biopsies show widely spaced myelin lamellae, with the wide spacing and demyelination attributed to the antibody properties of the IgM paraprotein. The slow progression is fortunate because treatment is difficult. Although success has been claimed for chlorambucil and fludarabine, convincing evidence of efficacy has yet to be provided. One small trial showed modest benefit from the anti-CD20 B cell marker rituximab and a larger trial is under way.
Other rare syndromes of particular neuropathies associated with paraproteins having interesting and potentially relevant autoantibodies are gradually emerging. In the CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies), antibodies are present against gangliosides with two sialic acid groups (disialosyl). The neuropathy is mixed axonal and demyelinating. The condition is so rare that it is not possible to make firm statements about treatment, but it can be very disabling and intravenous immunoglobulin can produce striking repeated short-term benefit. It is likely that other MGUS-associated neuropathies are due to as yet unidentified antibody properties of their paraproteins.
Lyme borreliosis
Lyme borreliosis is a multisystem disease caused by tick-borne spirochaetes belonging to the genus Borrelia (see Chapter 7.6.32). About 3 months after infection and without necessarily having had a preceding rash or arthritis, a small proportion of infected patients develop lymphocytic meningitis, facial palsy, painful radicular symptoms, and rarely a more severe generalized asymmetrical polyradiculoneuropathy. Some develop peripheral nerve lesions without ever having symptomatic meningitis. Serum antibodies to Borrelia are helpful in diagnosis but are common in endemic areas. In a hospital setting measurement of serum/cerebrospinal fluid antibody index is very specific but does not detect all cases. Nerve biopsies are not usually needed to make the diagnosis but do show extensive inflammatory infiltrates although the spirochaetes are not identifiable. Treatment is usually given in the form of parenteral penicillin or ceftriaxone but oral doxycycline is a possible alternative for mild cases.
HIV infection
A variety of neuropathies may be related to HIV-1 infection, particularly types tending to occur in different phases of the disease. At the time of seroconversion or soon afterwards Guillain–Barré syndrome, CIDP or multifocal vasculitic neuropathy may develop and precede other features of HIV infection. In the later AIDS phase, a distal symmetrical polyneuropathy is common. It is a slowly progressive disorder that may be painful and has to be distinguished from the toxic neuropathy produced by reverse transcriptase inhibitors mentioned earlier. In advanced cases an aggressive lumbosacral polyradiculoneuropathy from cytomegalovirus infection is encountered. HIV infection and its treatment are discussed in Chapter 7.5.23.
Sarcoid neuropathy
Facial palsy is the most common peripheral nerve manifestation of sarcoidosis (see Chapter 18.12). It may be bilateral and accompanied by uveitis and parotitis. Less commonly subacute or fluctuating multiple cranial nerve palsies occur. More rarely, almost any pattern of peripheral neuropathy has been seen, including multiple mononeuropathy and a Guillain–Barré syndrome-like picture, albeit usually more subacute. Other manifestations of sarcoidosis, such as erythema nodosum, arthritis, enlarged lymph nodes, uveitis, and abnormal chest radiographs, are not always present and the diagnosis has to be considered in a wide range of neuropathies. The cerebrospinal fluid is abnormal in about half the patients with peripheral nerve disorders due to sarcoidosis. If an accessible nerve can be biopsied, sarcoid granulomas in the nerve tissue clinch the diagnosis. Corticosteroids are the mainstay of treatment and their use is usually justified in patients with significant peripheral nerve involvement.
Diphtheritic neuropathy
Diphtheria (Chapter 7.6.1) used to be a serious, even fatal, disease of children. It was almost completely prevented in children by the advent of immunization. As immunity wanes, occasional cases are now seen in adults. It is most commonly caused by infection of the pharynx, occasionally by infection of wounds. Peripheral neuropathy is caused by the release of an exotoxin that interferes with Schwann cell function, probably by affecting protein synthesis, and produces segmental demyelination. The nerves are not invaded by the bacterium. In pharyngeal infection patients develop numbness of the tongue and face and a bulbar palsy, between 2 and 7 weeks after the infection. The bulbar palsy and respiratory involvement may be so severe as to require artificial ventilation. Paralysis of accommodation and sometimes of the external ocular muscles may occur. Weakness and sensory loss then develop in the limbs, sometimes as the bulbar palsy is beginning to improve. The disease also causes myocarditis. Nerve conduction studies show slowing of motor nerve conduction. The cerebrospinal fluid protein concentration becomes increased and the cell count may be raised. In particular in those cases with a normal cell count, there is a possibility of confusion with Guillain–Barré syndrome. Diagnosis can be made by culturing Corynebacterium diphtheriae from the throat, or identifying its toxin or DNA in throat swabs. Treatment is supportive because it is doubtful whether giving antitoxin will help once the peripheral neuropathy has developed.
Vasculitic neuropathy
Vasculitic neuropathy usually presents as a painful mononeuropathy or multiple mononeuropathy, but can present as a symmetrical polyneuropathy, and pain is sometimes absent. More commonly pain develops in the course of an established vasculitic disorder. Peripheral nerve involvement is characteristic and common in polyarteritis nodosa and Churg–Strauss syndrome. It also occurs in Wegener’s granulomatosis, hypersensitivity vasculitis, rheumatoid arthritis, relapsing polychondritis, and systemic lupus erythematosus. In rheumatoid arthritis, carpal tunnel syndrome and ulnar nerve lesions due to joint derangement are the most common peripheral nerve manifestations, but a florid multiple mononeuropathy and sometimes a slowly distal sensory neuropathy, or one restricted to the digital nerves, also occurs. In some cases vasculitic neuropathy heralds the identification of an underlying carcinoma or lymphoma. In rare cases, vasculitis is confined to nerves not only at presentation but also during follow-up, a condition called nonsystemic vasculitic neuropathy. Vasculitic neuropathy may be diagnosed from the clinical picture, if it is typical, such as multiple mononeuropathy in Churg–Strauss syndrome, or from the clinical picture and antineutrophil cytoplasmic antibodies in polyarteritis nodosa.
Often the diagnosis has been or can be made by biopsy of another affected tissue. If the diagnosis is in doubt biopsy of an affected nerve will usually reveal evidence of vasculitis, including inflammatory cell infiltration, occlusion, and fibrinoid necrosis of the epineurial blood vessels. To achieve maximum benefit from a nerve biopsy, it needs to be removed without crushing the tissue, processed with special techniques, and interpreted by an experienced observer, so it is best performed in specialist centres. Detection of vasculitis is one of the principal reasons for performing a nerve biopsy. Treatment of vasculitic neuropathy is the same as the treatment for the underlying disorder. Corticosteroids in the form of oral prednisolone are the mainstay of treatment. In many, especially severe cases, an immunosuppressive agent is also given. A regimen of oral or intravenous cyclophosphamide for 3 months followed by azathioprine is commonly used.
Sjögren’s syndrome is another cause of a vasculitic neuropathy but it also causes an ataxic sensory neuropathy related to dorsal root ganglionitis and a painful small fibre neuropathy (see below). Sometimes the trigeminal ganglion is affected in isolation.
Neoplastic and paraneoplastic neuropathy
Direct invasion of cranial nerves or spinal roots may occur in cases of malignant infiltration of the meninges and of the cervical and lumbosacral plexus from local malignancies. Malignant infiltration is usually painful. Infiltration of peripheral nerve trunks is seen most commonly from malignant lymphomas. Rarely, generalized infiltration may occur to produce a multiple mononeuropathy or even an acute neuropathy resembling Guillain–Barré syndrome.
Peripheral neuropathy may develop as a nonmetastatic, ‘paraneoplastic’ complication of carcinoma, most often bronchial or gastric, and very occasionally with lymphoma. The occurrence of a number of autoantibodies specific for these paraneoplastic manifestations makes it likely that it is an autoimmune condition. The underlying neoplasm often pursues an unusually indolent course, suggesting that the autoimmune process is holding the neoplasm in check. Perhaps for this reason, the neuropathy may antedate the discovery of the carcinoma by as much as 2 or 3 years. A wide variety of clinical pictures has been reported. A characteristic picture is the subacute sensory neuronopathy associated with a small cell lung carcinoma and antibodies to a nuclear protein called Hu. However, subacute sensory neuronopathy also occurs in association with many other neoplasms. Carcinoma of the bronchus is associated with other types of neuropathy, including a slowly progressive mixed sensory and motor neuropathy. Paraneoplastic neurological syndromes often occur in combinations. Gynaecological cancers are particularly associated with a cerebellar syndrome and antibodies to Purkinje cells (anti-Yo antibodies). Peripheral neuropathy may be part of this syndrome. Anti-Hu antibodies are often associated with limbic encephalitis as well as peripheral neuropathy. Paraneoplastic neuropathies may regress after removal of the underlying tumour, but may also not benefit. In a small number of cases in which treatment has been started very early, immunotherapy with corticosteroids, intravenous immunoglobulin, or plasma exchange has been followed by improvement of the neuropathy.
Genetic neuropathies
Porphyria (see also Chapter 12.5)
A predominantly motor neuropathy may complicate acute attacks in the autosomal dominant disorders of acute intermittent and variegated porphyria and hereditary coproporphyria, and in the recessively inherited δ-aminolaevulinic acid dehydratase deficiency. The neuropathy is usually preceded by colicky abdominal pain and mental disturbances including confusion, psychosis, and epilepsy. It develops acutely and resembles Guillain–Barré syndrome. It is often predominantly proximal, affects the motor more than sensory nerves and may affect the cranial nerves. The tendon reflexes are reduced in keeping with the weakness. Minor sensory symptoms including patchy paraesthesiae occur. Autonomic features include tachycardia, hypertension, pupillary dilatation, constipation, and sweating. Muscle atrophy due to axonal degeneration may be severe so that recovery is slow and often incomplete.
Attacks may be provoked by a variety of drugs, including barbiturates, sulphonamides, and the contraceptive pill, alcohol, and starvation (see Chapter 12.5). Prevention of attacks by the avoidance of precipitating factors is essential. Acute attacks should be treated with intravenous glucose and haematin to reduce the formation of porphyrin precursors.
Familial amyloid polyneuropathy
In addition to the axonal polyneuropathy that occurs in AL amyloid, a number of inherited amyloid neuropathies have been recognized. The most common are those related to point mutations in the gene for transthyretin, formerly known as prealbumin. The most common of these mutations is the Portuguese type where there is a substitution of valine for methionine in the transthyretin molecule. The neuropathy begins with the involvement of small nerve fibres, leading to a distal loss of pain and temperature sensation and autonomic failure. Spontaneous pain is often a feature and a mutilating acropathy frequently develops. The onset is commonly in the fourth or fifth decade and the disorder is slowly progressive, leading to death within about 10 years. Transthyretin is produced mainly in the liver and liver transplantation may halt progression of the disease. The same mutation occurs in Sweden, Japan, and other parts of the world, but the phenotype in these other communities varies. The neuropathy may not develop until the sixth decade or later and may sometimes have features of CIDP. Hereditary amyloid neuropathy can also be caused by mutations in the gene for other proteins and these have differing clinical features. In the Iowa form, the amyloid is derived from a mutated form of apolipoprotein A1 and causes a painful predominantly sensory neuropathy. In the Finnish form, there is a mutation in the gene for the plasma protein gelsolin, and the neuropathy affects the cranial nerves and is associated with a corneal lattice dystrophy.
Charcot–Marie–Tooth disease
Charcot–Marie–Tooth (hereditary motor and sensory neuropathy, peroneal muscular atrophy) disease usually presents during childhood or adolescence with difficulty in walking or because of foot deformity. It is genetically heterogeneous. Charcot–Marie–Tooth disease type 1 (CMT1) is caused by a demyelinating neuropathy with markedly slowed nerve conduction velocities (ulnar nerve motor conduction velocity <38 m/s). Charcot–Marie–Tooth disease type 2 (CMT2) is due to an axonal neuropathy with relatively preserved conduction velocities (ulnar nerve motor conduction velocity >38 m/s). Both CMT1 and CMT2 are themselves genetically heterogeneous. There is also a less common X-linked form, which may be demyelinating or axonal, in which the nerve conduction velocities are intermediate.
The clinical pictures of all three general forms of CMT are similar. Foot deformity is common and consists of a high arch, or pes cavus, and clawing of the toes, sometimes with an equinovarus deformity. Muscle weakness tends to affect the lower leg muscles and may give rise to bilateral foot drop with a ‘steppage’ gait. The muscle wasting is often restricted to below the knees, producing a ‘stork’ or ‘inverted champagne bottle’ leg appearance (Fig. 24.16.3). Weakness and wasting of the small hand muscles may appear later. The tendon reflexes become depressed or lost, and there is a variable degree of distal sensory loss. Progress of the disease is slow and cases with little disability or that are asymptomatic are common.
The most common from of CMT is CMT1a, accounting for 70% of all cases. It is caused by duplication of the gene for peripheral myelin protein 22 (PMP22). The onset is most frequently in the first decade. Foot deformity and scoliosis occur more often than in CMT2, sensory loss and ataxia tend to be greater, and generalized tendon areflexia is usual. Weakness in the hands appears earlier. The peripheral nerves may be thickened because of an excess of connective tissue and reduplication of the Schwann cells concentrically around axons to form the appearance in cross-section of an ‘onion bulb’. Cases with ataxia and upper limb tremor are sometimes referred to as the Roussy–Lévy syndrome. Other causes of CMT1 include mutations of PMP22 and also of the gene that codes for P0, the major peripheral nerve myelin structural glycoprotein. The most common genetic cause of CMT2 is a mutation in the gene for mitofusin 2 (MFN2) but this accounts for only 20% of cases. Other causes include mutations in the genes for P0 or the neurofilament light chain (NEFL). X-linked CMT is due to mutations in the gene for connexin 32; women may be asymptomatic or only mildly affected by an axonal neuropathy whereas men usually have a somewhat multifocal demyelinating neuropathy. The genetic diagnosis of CMT is in a rapid stage of development. The list of responsible genes is already much longer than the common examples mentioned and rare autosomal recessive forms occur. The diagnosis of the common gene mutations can usually be made from the clinical picture, neurophysiological studies, and molecular genetic tests. If not it may be necessary to resort to nerve biopsy.
Affected individuals may be helped by the use of orthotic appliances and sometimes by surgical correction of foot deformity or tendon transfer. After successful treatment of mouse models for CMT1a, trials of vitamin C, an essential cofactor for Schwann cell cultures, are under way in the human disease. Preliminary results are not encouraging.
Hereditary neuropathy with liability to pressure palsies
This is an autosomal dominant disorder in which affected individuals develop recurrent focal peripheral nerve or brachial plexus lesions produced by compression or stretch injury. It has been shown to usually be caused by a deletion of the PMP22 gene which is duplicated in CMT1a. Nerve fibres show focal regions of myelin thickening resembling little sausages, leading to the term ‘tomaculous neuropathy’ from the Latin ‘tomacula’ which means sausages.
Congenital hypomyelinating neuropathy
Rarely CMT presents in infancy or early childhood with a very severe progressive sensory and motor neuropathy and extremely slow nerve-conduction velocities. This used to be called Dejerine–Sottas disease or CMT3. Pathologically, there is hypomyelination and extensive demyelination in the peripheral nerves, with onion bulbs and a thickened peripheral nerve trunk. These cases may be due to new mutations of PMP22, early growth response gene 2 (EGR2), or other genes.