413 Postgrad Med J: first published as 10.1136/pgmj.35.405.413 on 1 July 1959. Downloaded from

POLYNEURITIS By G. S. GRAVESON, M.A., M.D., F.R.C.P. Consultant Neurologist, Wessex Regional Hospital Board (From the Southampton General Hospital)

Diseases affecting the lower motor and sensory acid and vitamin B.I2. Thiamine is a constituent neurones, diffusely and usually symmetrically, are of the coenzyme cocarboxylase, which is necessary grouped together under the title polyneuritis. The for the oxidation of pyruvic acid formed in the term is imprecise, for many of these diseases affect metabolism of glucose by cells. It is also structures other than peripheral , e.g. concerned in the synthesis of acetylocholine in spinal nerve cells, roots and muscles, and few of nerve fibres. Its deficiency, therefore, results in them are really inflammatory disorders. To over- neuronal degeneration and the accumulation of an come this inaccuracy, such terms as polyradiculo- excess of pyruvate in the blood. This may be neuropathy and neuromyopathy have been coined present in the fasting state or it may be brought but the older word still serves, with better out by a loading dose of glucose. Joiner, McArdle euphony perhaps, provided it is used merely in and Thompson (1950) describe the use of such aProtected by copyright. the sense of a condition in which lesions of peri- 'pyruvate metabolism test ' in the investigation of pheral nerves occur. Its retention may be ad- cases of polyneuritis. Lack of thiamine may be a visable, too, until such time as the pathogenesis of contributory factor in the polyneuritis of chronic the various types of the disease have been more alcoholism and in those cases which complicate fully elucidated. From a clinical viewpoint, the chronic disease of the gastro-intestinal tract. Its disease is a syndrome, easily recognized as such, action as a coenzyme has to be integrated with that but often requiring much time and care in the of another enzyme, (Sinclair, I956). investigation of its aetiology. Classification of the This substance is thought to be formed in the disorder on aetiological lines, e.g. toxic, metabolic, liver and it has the property of forming stable infective types, etc., is usual in neurological texts, compounds with a variety of organic and inorganic but this cuts across pathogenesis and it seems substances, e.g. arsenic, mercury, carbon disul- preferable to attempt a division on pathological phide, acetaldehyde and acetoacetate. Sinclair grounds. Three main groups may be distin- suggests that the polyneuritis produced by such http://pmj.bmj.com/ guished: (a) parenchymatous, (b) interstitial, and substances is similar to that of thiamine deficiency (c) vascular (Greenfield, 1958). in so far as the same underlying enzyme systems are affected. He also thinks that diabetic poly- (a) Parenchymatous Types of Polyneuritis neuritis may be in part due to the inactivation of These are two in number: (i) those in which the lipoic acid by ketones. neurone degenerates as a whole or in its peripheral Pantothenic acid as part of coenzyme A is

part-primary neuronal degeneration; and (ii) those intimately concerned with the metabolism of on September 30, 2021 by guest. in which demyelination of the nerve fibres occurs pyruvate as well as thiamine, but it is so widely in segments-segmental demyelinative neuropathy distributed in food that its deficiency in man is (Fisher and Adams, 1956). The first comprises unsubstantiated. It has been claimed to cure the those types of polyneuritis in which some meta- ' burning feet' syndrome, but this is doubtful, bolic or dietetic deficiency results in degenerative and it has been used with apparent benefit in the or atrophic changes. The classical example is treatment of vestibular neurone damage caused beri-beri, and it was from experimental work in by streptomycin. connection with this disease that the B group of Pyridoxine deficiency in animals produces inter vitamins was discovered. In animals, several of alia epileptic fits and peripheral nerve degenera- these vitamins seem necessary for the preservation tion. In man this vitamin forms a stable com- of an intact peripheral nervous system; in man, pound with isoniazid (I.N.A.H.), which blocks its only five are of relevant clinical importance- action. Hence a polyneuritis may occur and, in thiamine, pantothenic acid, pyridoxine, nicotinic fact, in this country, I.N.A.H. is probably the 414 POSTGRADUATE MEDICAL JOURNAL July 1959 Postgrad Med J: first published as 10.1136/pgmj.35.405.413 on 1 July 1959. Downloaded from commonest cause of a chemically induced Refsum's disease and primary of nerves neuropathy. such as in and trypanosomiasis. Deficiencies of nicotinic acid and vitamin B.I2 also produce peripheral neuropathies, usually (c) Vascular Types of Polyneuritis overshadowed by spinal cord changes, in pellagra Peripheral nerves may be damaged in generalized and subacute combined degeneration of the cord vascular disease of the limbs-atheroma, Buerger's respectively, but the exact pathogenesis is not yet disease, frostbite and immersion foot. The known. Even less is known of the cause of the nutrient arteries of nerves may, however, be polyneuritis associated with carcinoma, reticulosis specifically affected, for example, in polyarteritis and sarcoidosis, but it is also thought to be due to nodosa. This results in necrosis of fibres distal some metabolic disturbance. to the segment affected. Such changes may be Finally, primary degeneration of peripheral diffuse, giving rise to a symmetrical polyneuritis, nerves may occur as an hereditary disease-pero- or they may be scattered irregularly to produce a neal muscular atrophy (Charcot-Marie-Tooth's series of peripheral nerve palsies-mononeuritis disease). Presumably again the fault is biochemi- multiplex. cal, though nothing is known of its nature. This grouping of types of polyneuritis cannot The second type of parenchymatous poly- be extended to all varieties of the disease. So neuritis is segmental demyelinative neuropathy. little is known of the pathogenesis of some that In this condition, involvement of nerve fibres is accurate classification is impossible. This applies patchy and in the early stages limited to internodal in particular to one of the most common-diabetic segments of the myelin sheath, with preservation polyneuritis. The pathological changes here of the sheath proximal and distal to the lesion. suggest that possibly all three types may be seen in Axon degeneration does not occur until a late this disease. The accompanying table summarizes

stage is reached and, therefore, in less severe cases this classification and is modified from GreenfieldProtected by copyright. recovery can occur. This curious pattern of in- (1958). volvement probably occurs because the primary toxic damage is to the sheath of Schwann and it is Clinical Diagnosis seen in the polyneuritis of , lead and By and large, polyneuritis presents no great acute porphyria. problem in diagnosis. Variations in symptoms and signs occur, of course, between different types (b) Interstitial Types of Polyneuritis of the disease but these are quantitative rather This group comprises of the peri- than qualitative and depend on the tempo of events and endoneurial tissues and the pressure effects of and relative differences in the involvement of acute and chronic oedema on nerves and spinal motor and sensory fibres. Only rarely is the roots. Its most important varieties are those distribution of lesions of diagnostic help, e.g. the diseases which appear to have an allergic aetiology peculiar ciliary and palatal of diphtheritic

-acute infective polyneuritis (the Guillain-Barre polyneuritis. This discussion, therefore, will be http://pmj.bmj.com/ syndrome), polyneuritis complicating serum and mainly concerned with general principles only. vaccine therapy and possibly acute brachial radi- Motor nerve involvement produces those features culitis (neuralgic amyotrophy). Only in the first of a lower motor neurone lesion-weakness, of these have adequate pathological studies been wasting and a diminution or loss of tendon reflexes. made (Haymaker and Kernohan, 1949). The Sensory nerve involvement is more variable in its initial change is one of oedema of the roots and presentation depending on the type of fibre proximal parts of the spinal nerves, followed by damaged. Symptoms consist of , paraes- degeneration of myelin sheaths and axons and thesiae, numbness and unsteadiness, objectively in on September 30, 2021 by guest. later by lymphocytic infiltration. The allergic loss or impairment of the modalities of touch, hypothesis has been strengthened by the work of pain, temperature, vibration and joint sense, to- Waksman and Adams (I955, 1956), who were able gether with an increase of muscle tenderness. In to produce an experimental allergic neuritis in most types of polyneuritis, the longest nerve animals by the injection of homologous peripheral fibres are earliest affected so that these symptoms nerve tissue with suitable adjuvants. The appear distally in the extremities and usually in the sequence of pathological events was similar to that legs before the arms. On the motor side this gives in acute infective polyneuritis. It is in this group rise to a bilateral foot drop with a steppage gait, of disorders that steroid therapy has proved of and in the upper limbs to weakness of hand great value. muscles and wrist and finger drop. On the Other rare conditions of interstitial type are the sensory side a characteristic glove and stocking polyneuritis of primary amyloidosis, the hereditary type of loss occurs. Rarely, impairment of joint hypertrophic polyneuritis of Dejerine and Sottas, sense may overshadow other types of sensory loss 1959 GRAVESON: Polyneuritis 415 July Postgrad Med J: first published as 10.1136/pgmj.35.405.413 on 1 July 1959. Downloaded from CLASSIFICATION OF TYPES OF POLYNEURITIS curves and and also at times a (a) Parenchymatous muscle biopsy examination. Conversely, other (i) Primary Neuronal Degeneration types of polyneuritis present as sensory disorders (a) Disturbance of pyruvate oxidation in the neurone. with little or no muscle weakness, e.g. diabetes and Beri-beri, chronic alcoholism, arsenic and subacute combined degeneration of the cord. Such mercury poisoning, polyneuritis of gastro- intestinal disease. discrepancy between motor and sensory involve- (b) Other B vitamin deficiencies. ment may therefore be a useful clue to causative Pellagra, subacute combined degeneration of diagnosis. Speed of onset may likewise aid the cord, pyridoxine deficiency (I.N.A.H. differentiation-acute poisoning and allergic dis- poisoning). ? pantothenic acid deficiency (streptomycin orders may give rise to widespread signs in a poisoning). matter of hours or days, chronic metabolic de- (c) Less well understood metabolic disorders of the ficiencies and chronic intoxications produce poly- neurone. neuritis developing slowly over weeks or months. Polyneuritis associated with carcinoma, reticu- losis and sarcoidosis. Palpation of peripheral nerves deserves em- (d) Hereditary neuropathies due to abiotrophy or phasis for it is often omitted. Tenderness may be nutritional failure of the neurone. a useful corroborative sign and enlargement a vital Peroneal muscular atrophy (Charcot-Marie- diagnostic one. Tooth's disease). Cranial nerve involvement, especially the Hereditary sensory neuropathy (Denny Brown). seventh, is a not infrequent addition to peripheral (2) Segmental Demyelinative Neuropathy neuritis-especially in acute infective polyneuritis (Toxins chiefly affecting the sheath of Schwann and and sarcoidosis-and mental changes may also myelin.) occur. Heart failure is a hazard common to some Diphtheria, lead, acute porphyria. types-beri-beri, diphtheria and acute infective (b) Interstitial polyneuritis. Protected by copyright. (a) Allergic and post-infectious polyneuritis (causing Pathological investigations play an all-important oedema + of nerves). cases. Acute infective polyneuritis, serum and vaccine part in the diagnosis of obscure C.S.F. neuritis, ? acute brachial radiculitis (neuralgic examination usually reveals a high protein content amyotrophy). without any increase in cells, but may be normal (b) Metabolic disorders. even in acute cases. Urine examination confirms Hereditary hypertrophic polyneuritis (Dejerine and Sottas), Refsum's disease, primary amy- a diagnosis of diabetes, porphyria and some exo- loidosis. genous poisons. Carcinomatous neuropathy must (c) Interstitial inflammation of nerves. always be considered in the middle-aged. Bron- Leprosy, trypanosomiasis, pyogenic. chial carcinoma is the most frequent cause and a (c) Vascular routine chest X-ray is necessary. In such cases, Polyarteritis nodosa, atheroma, Buerger's however, the polyneuritis may antedate the ap- disease, ? diabetic polyneuritis. pearance of the cancer, so that serial films may be

required. Chest films may also reveal evidence of http://pmj.bmj.com/ and give rise to a sensory ataxia-a pseudo-tabetic reticulosis and sarcoidosis. Subacute combined picture occasionally seen in diabetes, alcoholism degeneration of the cord may begin with symptoms and carcinoma, and in the hereditary sensory of a polyneuritis before there are any changes in neuropathy of Denny Brown. In long-standing the peripheral blood or bone marrow. In sus- cases of sensory loss, trophic ulceration of the feet pected cases, who will always show a histamine- may occur. fast achlorhydria, the diagnosis can be made either Usually, disorder of motor and sensory function by an estimation of the serum B.I2 level (values proceeds concurrently and to a more or less equal below ioo j*g. per ml. indicate vitamin B.iz on September 30, 2021 by guest. extent, but in some conditions one type of fibre deficiency but are usually very much lower in is predominantly involved so that an almost pure S.A.C.D.) or by means of a radioactive B.I2 test. motor or sensory syndrome is produced. Motor Briefly, in this a known quantity, approximately polyneuritis, for example, characterizes some cases i mgm., of radioactive B.I2 is taken by mouth of acute infective polyneuritis, acute porphyria and and the amounts subsequently excreted in urine carcinoma, but in most of these conditions, even and faeces are estimated. In S.A.C.D. little or when sensory symptoms are absent, muscle no absorption occurs from the gut, so that at tenderness is always increased. Chronic cases of least 8o per cent. is recovered from the faeces. motor polyneuritis may present the most difficult These are most useful tests to make at a stage in diagnostic problems and their differentiation from the disease when treatment is usually fully such diseases as progressive muscular atrophy, curative. polymyositis and muscular dystrophy may require Gastro-intestinal function may occasionally need electrodiagnosis by means of intensity duration investigation-polyneuritis occasionally compli- 4I6 POSTGRADUATE MEDICAL JOURNAL JUly 1959Postgrad Med J: first published as 10.1136/pgmj.35.405.413 on 1 July 1959. Downloaded from cating such conditions as steatorrhoea, ulcerative cases the spread of the disease is self-limited-re- colitis, tuberculosis and g4strectomy. covery begins and eventually, after months, is Finally, when other tests fail, a biopsy of a complete, except in elderly patients where some digital nerve in the foot may be required and is degree of permanent may occasionally be diagnostic in such conditions as primary amy- seen. Relapses and recurrences of the disease loidosis and hypertrophic polyneuritis. sometimes happen. Prognosis has been greatly Treatment of polyneuritis must be both sympto- changed in recent years by (i) steroid therapy and matic and where possible specific. General (ii) methods of artificial respiration to tide patients measures include suitable analgesics for pain, over the acute phase. In a majority of patients, correct splintage for paralysed limbs, physio- though not all, the disease seems to be controlled therapy and walking appliances where necessary. by steroid hormones. In some a quite dramatic Specific therapy to correct metabolic or vitamin disappearance of weakness occurs, in others im- deficiency is often difficult to assess and has led to provement does not begin until the second week of much controversy, due largely to an insufficient therapy, whilst in a minority the disease progresses realization that where nerve fibres are destroyed, in spite oftreatment (Jackson, Miller and Schapira, recovery can only occur by the long process of re- 1957; Graveson, 1957). To be effective, it must generation, and this cannot be influenced by any be given at the earliest possible opportunity before known remedy. Hence the effects of specific irreversible damage has occurred and in large therapy can only be obvious in reversible lesions amounts. Very severe cases require parenteral and this emphasizes the need for early diagnosis. therapy either with hydrocortisone sodium suc- It is usual to employ multi-vitamin B preparations cinate IOO mg. intravenously twice daily or long either orally or by injection, rather than single acting A.C.T.H. 40 units daily intramuscularly for vitamins. Special antidotes to particular poisons the first few days. Less severe cases will respond

are few, but mention must be made of the use of to oral treatment with cortisone or prednisone.Protected by copyright. dimercaprol (B.A.L.) in arsenic and metallic Cortisone is given in doses of 300 mg. daily for poisoning and in those cases of polyneuritis with a two days, then 20o mg. daily for two days, con- disturbed pyruvate metabolism which do not tinuing thereafter for two to three weeks with respond to thiamine. IOO mg. daily. The comparable doses of pred- In allergic types of polyneuritis and in polyar- nisone are 6o, 40 and 20 mg. daily. Improvement teritis nodosa, steroid therapy is necessary and will can best be judged in those muscles only slightly be discussed below. affected. When the drug is discontinued, weak- ness will recur within 24 to 48 hours if the disease Acute Infective Polyneuritis process is still active and the drug has then to be A full discussion of particular types of poly- continued for another week or two. The variable neuritis is beyond the scope of this article, but response to steroids suggests that the disease may some special mention must be made of this disease not be an entity but a syndrome of multiple -the commonest cause of polyneuritis in this aetiology. http://pmj.bmj.com/ country. Reference has already been made to its Patients with respiratory and/or bulbar involve- probable allergic aetiology. Frequently, it begins ment should be transferred to respiratory units as a' second illness,' following by a week or more where possible, there to undergo artificial respira- some seemingly banal infection usually of the tion when needed, either in a tank respirator or by respiratory tract. The onset is sudden, with fever intermittent positive pressure respiration through and backache, followed within a day or two by a tracheotomy. By these means, the mortality of in the limbs, muscular weakness and distal this condition has in recent years been considerably

on September 30, 2021 by guest. sensory symptoms. Unlike most other types of reduced. polyneuritis, the weakness may start proximally and spread distally. In other cases paralysis BIBLIOGRAPHY the feet to involve trunk, arms, head FISHER, C. M., and ADAMS, R. D. (i956), . Neuropath., I5, 24 . ascends from GRAVESON, G. S. (I957), Lancet, i, 340. and neck (Landry type). Sensory symptoms are GREENFIELD, J. G. (1958), in 'Neuropathology' by Greenfield, absent, though Blackwood, Meyer, McMenemy and Norman. E. Arnold Ltd., often minimal and sometimes London. muscle tenderness is always increased. The speed HAYMAKER, W., and KERNOHAN, J. W. (1949), Medicine, of evolution of the paralysis varies considerably Baltimore, 28, 59. JACKSON, R. H., MILLER, H. G., and SCHAPIRA, K. (I957), from mild cases with progressive weakness over a Brit. med. Y., 1, 480. period of weeks to fulminating cases dying from JOINER, C. L., McARDLE, B., and T]HOMPSON, R. H. S. (1950), Brain, 73, 431. respiratory failure in a matter of days. C.S.F. SINCLAIR, H. M. (I956), Brit. med. Bull., I2, I8. examination usually shows an increase of protein WAKSMAN, B. H., and ADAMS, R. D. (I5ss), J. exp. Med., 102, 213. but may be normal in the early stage. Occasionally WAKSMAN, B. H., and ADAMS, R. D. (I956), Y. Neuopath., the cell content may be increased. In non-fatal 15, 293-