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Chapter XIX

Contents

CHAPTER XIX

Peripheral Neuritis

George D. Gammon, M.D.

The incidence of neuritis in World War II was not high, and the condition, statistically at least, was of relatively minor concern among the medical and surgical problems of the Army. Practically, its importance arose chiefly from the severity of the invalidism it produced. Several new types were recognized, but no new causative agents were discovered. Ultimately, the greater number of cases were recognized as being due to diphtheria. This recognition was due to the growing familiarity with clinical manifestations, to the improvement in confirmatory diagnostic tests, and to the rising incidence of diphtheria toward the end of the war, particularly in Europe. Experience brought, too, a wider realization that an albuminocytologic dissociation in the spinal fluid could occur in a wide variety of neuritides and that this dissociation, of itself, did not establish a diagnosis of infectious polyneuritis of the Guillain-Barré type.

The first part of this chapter is an account of the problems as they appeared in the various theaters during the course of the war; the second part is an attempt to characterize the various syndromes and to emphasize the difference between them, in the conviction that clinical distinctions are themselves of value and must be maintained when causative agents cannot be defined.

Part I. Clinical Experience

Observations made early in World War II, cited by McGuinness,1 indicated that from 10 to 76 percent of American servicemen were susceptible to diphtheria, depending on their prior residence. Since it was known that they would enter foreign areas in which the disease was endemic, the reports of cases in U.S. troops from the Pacific areas and the China-Burma-India and Mediterranean theaters were not unexpected. In these regions, however, the problem of proving a suspected diagnosis was fraught with difficulties. The demonstration of virulent micro-organisms in lesions of the throat or the skin was not easy, nor was the environment of forward combat areas favorable for doing such work. In all, 5,724 cases of diphtheria, with 125 deaths, were reported from January 1942 through December 1945.

1McGuinness, Aims C.: Diphtheria. In Medical Department, United States Army. Preventive Medicine in World War II. Volume IV. Communicable Diseases. Washington: U.S. Government Printing Office, 1958. pp. 167-189.


514

DIFFERENTIAL DIAGNOSIS

Correspondingly difficult, particularly during the early years of the war, was the differential diagnosis of the nature of a neuritis. In the Tropics, paralysis was associated with cutaneous ulcers and with malaria, conditions generally unfamiliar to American medical officers. In Africa and Italy, the albuminocytologic dissociation was a frequent finding. Cases were sometimes ascribed to infectious polyneuritis on this basis alone until the same dissociation had been repeatedly demonstrated in proved cases of diphtheria, in late poliomyelitis, and in other conditions, poorly defined. In some syndromes, the etiology was, and remains, obscure.

Typical diagnostic problems are illustrated in Bronson's report2 on two series of patients; the first, from the 4th General Hospital in Melbourne, Australia, in 1943, dealing with 13 cases of neuropathy in marines who had invaded Guadalcanal, and the second, from Moore General Hospital, Swannanoa, N.C., in 1945, dealing with 60 "similar cases" with skin diseases. The marines, without much contact with natives or foe, had developed severe sore throat and later a polyneuritis. There was no evidence to substantiate the diagnosis of diphtheria from cultural studies, Schick tests, or the titration of diphtheria antitoxin in their serums. Actually, the amounts of antitoxin found in the patients were identical with those found in the control cases. Attempts to isolate viruses were likewise unsuccessful, and pooled nasopharyngeal washings inoculated into embryonated eggs, spinal fluid inoculated intracerebrally into mice, and stools inoculated intraperitoneally into monkeys failed to provoke disease. The onset of the neuropathy in these 13 cases occurred from 3 to 60 days after the sore throat, reaching a maximum in 23 to 114 days, with recovery in 5 to 8 months (average 7 months).

In Bronson's second series of 60 "similar cases" with skin diseases studied in 1945, diphtheria was proved in 7 and suspected in 5; no evidence was produced to suggest that the other 48 cases were caused by diphtheria. The neuropathy was slow in developing and in subsiding to a complete recovery and was accompanied by increased amounts of protein in the spinal fluid. Although admitting that these findings were not consistent with the picture of diphtheritic neuropathy, Bronson concluded that they were, in fact, unrelated to diphtheria. Weighing against this view was the evidence that other marines fighting alongside the troops originally studied by Bronson, and evacuated to a naval hospital ship, were proved to have diphtheria and diphtheritic neuritis by Norris and his associates,3 who identified Corynebacterium diphtheriae and who were among the first to recognize the character of the problem. Bronson's cases could not, in retrospect, be definitely

2Bronson, L. H.: Neurologic Disease Following Infections of Throat and Skin and Incidence of Diphtheritic Infections. Arch. Neurol. & Psychiat. 56: 558-566, November 1946.
3Norris, R. F., Kern, R. A., Schench, H. P., and Silcox, L. E.: Diphtheria in the Tropics; Report of 18 Cases on a United States Naval Hospital Ship. U.S. Nav. M. Bull. 42: 518-524, March 1944.


515

diagnosed, and they illustrated the difficulties in proving a diagnosis of diphtheritic neuritis.

Meanwhile Liebow, MacLean, Bumstead, and Welt4 reported on cutaneous diphtheria seen in 1943 and 1944 at the 39th General Hospital, Auckland, New Zealand, with an extensive review of the literature, and described many cases of neuritis. Oppel, Smith, Montanaro, and Tompsett5 of the 9th General Hospital, also in the Pacific, found virulent C. diphtheriae in various cutaneous lesions in one out of six individuals and noted that spread occurred from these patients regardless of isolation. They incriminated flies. These two studies, as well as others, emphasized the predominance of cutaneous over pharyngeal diphtheria. Oppel and his coworkers observed 9 cases of neuropathy in 210 cases of diphtheritic infection, an incidence of 4 percent.

In the China-Burma-India theater, an outstanding study of cutaneous diphtheria was made at the 20th General Hospital, Assam, India, by Livingood.6 As described in his letter of 9 October 1944 to the commanding officer of that hospital, the ulcerous skin lesions were suspected as diphtheritic as early as June 1944, although cultural proof was lacking. The development of typical postdiphtheritic neuritis in one patient and the death of another in cardiac failure substantiated this suspicion, and confirmation by cultural studies finally came in October 1944. Livingood reported on 140 cases, 61 with neuropathy. Gaskill's description7 on these neuropathic cases presented a clear and detailed summary which showed the neuropathy to be distinctive. In retrospect, this experience proved almost unique, since the cases were followed from onset to conclusion, and full advantage was taken of the opportunity to study and describe them (pp. 521 and 525). Many cases were also reported from the 69th General Hospital in this theater.8 Other excellent reports of diphtheritic neuritis seen early in the war, in patients evacuated from various theaters, were made by Perkins and Laufer9 with 21 cases, by Sampson10 with 20 cases, and by Copsey11 with 17 cases.

As troops with cutaneous diphtheria appeared in hospitals of the United States, the factor of contagion became a matter of concern. The Commission

4Liebow, A. A., MacLean, P. D., Bumstead, J. H., and Welt, L. C.: Tropical Ulcers and Cutaneous Diphtheria. Arch. Int. Med. 78: 255-295, September 1946.
5Oppel, T. W., Smith, J. J., Montanaro, A., and Tompsett, R. R.: Clinical Features of Diphtheria in the Tropics. [Official record.]
6Letters, Maj. Clarence S. Livingood, MC, Chief, Section of Dermatology and Syphilology, to Commanding Officer, 20th General Hospital, 9 Oct. 1944 and 25 Jan. 1945, subject: Cutaneous Diphtheria.
7Letter, Maj. Herbert S. Gaskill, MC, Chief, Neuropsychiatric Section, to Commanding Officer, 20th General Hospital, 18 Mar. 1945, subject: Preliminary Report on the Neuritis Complicating Cutaneous Diphtheria.
8Blumgart, H. L., and Pike, G. M.: History of Internal Medicine in India-Burma Theater. [Official record.]
9Perkins, R. F., and Laufer, M. W.: Clinical Study of Postdiphtheritic Polyneuritis. J. Nerv. & Ment. Dis. 104: 59-65, July 1946.
10Sampson, J. J.: Late Neuronitis Following Proved and Suspected Cutaneous, Faucial, and Wound Diphtheria. Am. J.M. Sc. 212: 432-448, October 1946.
11Copsey, H. G.: Symposium on Problems in Postwar Medicine; Postdiphtheritic Paralysis. M. Clin. North America 30: 445-450, March 1946.


516

on Meningococcal Meningitis, Army Epidemiological Board, from an extensive survey at Letterman and Moore General Hospitals, concluded that diphtheria was indeed a problem in the Pacific, that a large percentage of cases of polyneuritis in general hospitals were postdiphtheritic, and that the current clinical classification of polyneuritis was not satisfactory.12 Meanwhile, the skepticism of physicians in the Southwest Pacific Area, based upon failure to obtain laboratory confirmation of diphtheria, was gradually yielding to growing experience, as reported by Col. Benjamin M. Baker,13 MC, in 1944. Subsequently, measures were taken that resulted in a steady decline in the number of cases during that year. Liebow and his associates (p. 515) noted that, after the diphtheritic nature of certain tropical ulcers became apparent, there was not an instance of the neuritis of the type just discussed that could not be related either to the ulcers, to sore throat, or to proved diphtheritic pharyngitis or dermatitis. They concluded that the vast majority of neuritis seen in the Tropics was diphtheritic in origin. These views were incorporated in War Department Technical Bulletin (TB MED) 143, "Cutaneous Diphtheria," February 1945.

There were other types of neuropathy in the Pacific areas, however, that did not fit into this pattern. Harvey, Kuffler, and Tredway14 reported from the 118th General Hospital, Tolosa, Leyte, a group of 20 cases of unknown cause in which the manifestations were quite unlike those of diphtheritic neuritis but resembled the shoulder-girdle and peroneal paralysis described by Spillane. (See page 534.) Harvey15 also reported still another type, associated with attacks of malarial fever (p. 532). This was overt in 16 cases and found in milder form in 18 of 100 consecutive cases of malaria.

Another group of 40 cases of neuropathy was reported from the Philippines in 1945 by Pessin and Silverman.16 These appear to have shown diverse clinical manifestations and course. Over half the patients had gastrointestinal disturbances and 40 percent had infectious hepatitis; the authors postulated that both infection and vitamin deficiency were responsible for the paralysis.

Meanwhile, in Africa and Italy, the problem of neuropathy presented itself chiefly as an outbreak of what appeared to be infectious neuritis of the Guillain-Barré type. Maj. Joseph W. Johnson, Jr., MC, of the 300th General Hospital, examined many patients, collected case records, and

12Memorandum, Commission on Meningococcal Meningitis, Army Epidemiological Board, for The Surgeon General (through Brig. Gen. S. Bayne-Jones, Preventive Medicine Service, Office of The Surgeon General, 6 July 1945, subject: Diphtheria Infections at Letterman General Hospital, San Francisco, California, and at Moore General Hospital, Asheville, North Carolina.
13Letter, Col. Benjamin M. Baker, MC, Consultant in Medicine, to Brig. Gen. Earl Maxwell, Headquarters, U.S. Army Forces, South Pacific Area, 16 Mar. 1944.
14Harvey, A. M., Kuffler, S. W., and Tredway, J. B.: Peripheral Neuritis; Clinical and Physiological Observations on Series of 20 Cases of Unknown Etiology. Bull. Johns Hopkins Hosp. 77: 83-103, August 1945.
15Harvey, A. M.: Type of Neuritis Associated With Malarial Fever. Bull. Johns Hopkins Hosp. 75: 225-231, October 1944.
16Pessin, J., and Silverman, D.: Peripheral Neuritis in the Philippines. [Professional paper.]


517

analyzed the data, in a study that was finally embodied in two monographs. As a result of this focusing of attention upon the subject, the late Maj. Emanuel B. Schoenbach, MC, and the author were sent to Italy by the Commission on Neurotropic Virus Diseases of the Army Epidemiological Board shortly after the end of the war in Europe. Almost concurrently, Lt. Col. Aims C. McGuinness, MC, and Dr. J. Howard Mueller studied diphtheria in the European theater.17 In his report to the Surgeon, MTOUSA (Mediterranean (formerly North African) Theater of Operations, U.S. Army) of 2 February 1945, Major Johnson18 outlined the problems encountered. Cases of the so-called Guillain-Barré syndrome had appeared in North Africa; five cases were reported by Lt. Col. Morton H. Hand (cited by Johnson) in January 1944. Many additional cases were observed widely throughout the theater as summarized from the literature by Johnson, who reported another 15 cases of Guillain-Barré syndrome in April and still more in June 1944. In September 1944, the Guillain-Barré syndrome was made reportable to the Surgeon, NATOUSA (North African Theater of Operations, U.S. Army). Weinstein and Gersten19 had noted another type of shoulder-peroneal palsy. Lt. Col. Theodore J. C. Von Storch (quoted by Johnson) found after extensive investigation that neuropathy accounted for 1.5 percent of all the medical dispositions between Anzio and Casablanca in February 1944. Johnson20 presented evidence, based on 119 cases of the Guillain-Barré syndrome, indicating that the diagnoses had been made as a result of the finding of albuminocytologic dissociation in the spinal fluid without much, if any other, relation to the syndrome described by Guillain, Barré, and Strohl. From his extensive data, he concluded that "a majority of these cases seen in Italy were probably attributable to post-diphtheritic polyneuritis (58.06 percent)." He noted "that the diagnosis of diphtheria is not easy, its substantiation even more difficult, and that diphtheria recently has been atypical." He pointed out the great difficulty of properly evaluating such cases during active combat.

Johnson made a second report,21 1 July 1945, to the Surgeon, MTOUSA, based on restudy of the records of 155 patients, 31 percent of whom had been observed on his own service in a general hospital in the theater. He reclassified them (table 97) on the basis of the total clinical findings rather than on spinal fluid or other tests and concluded that here, as in the Pacific, diphtheria accounted for the major portion of the neuritides. It is noteworthy that, in 20 of the 90 cases with a typical diphtheria neuritis, no history of a

17See footnote 1, p. 513.
18Johnson, J. W., Jr.: Monograph on Infectious Polyneuritis, Part I, Report to the Surgeon, MTOUSA, 2 Feb. 1945.
19Weinstein, E. A., and Gersten, D.: An Unusual Type of Peripheral Neuropathy: Report of 13 Cases. M. Bull. North African Theat. Op. 1: 9-10, May 1944.
20(1) Johnson, J. W., Jr.: Infectious Polyneuritis-Diagnostic Criteria and Military Implications; Report of 15 Cases. M. Bull. Mediterranean Theat. Op. 2: 149-159, December 1944. (2) Johnson, J. W., Jr.: Some Unusual Complications of Diphtheria. J. Tennessee M.A. 40: 114-123, April 1947.
21Johnson, J. W., Jr.: Monograph on Infectious Polyneuritis, Part II, Report to the Surgeon, MTOUSA, 1 July 1945.


518

prodromal illness suggestive of diphtheria was recorded and that in 66 percent diphtheria had not been recognized until the development of the complication. Johnson commented on the British cases in the theater and on civilian cases in Italy. Of 397 patients with diphtheria in a hospital in Florence, neural complications developed in 90 to 95 percent, but myocardial complications in only 5 to 10 percent. He contrasted this with the very low incidence of neural complications (less than 1 percent) and the higher incidence (20 percent) of myocardial complications in the United States.

TABLE 97.-Reclassification (final) diagnoses of neuropathies, U.S. Army personnel in Mediterranean theater, during World War II

Original diagnosis

Number of diagnoses1

Percent of diagnoses

Reclassification diagnosis

Number of cases

Percent of cases

Guillain-Barré syndrome

73

41.71

Guillain-Barré syndrome

10

6.45

Landry's ascending paralysis

1

.57

Landry's ascending paralysis

0

0

Neuropathies due to-

 

 

Neuropathies due to-

 

 

    

Sulfonamides

1

.57

    

Sulfonamides

1

.64

    

Alcohol

2

1.14

    

Alcohol

2

1.29

    

Nutritional deficiencies

3

1.71

    

Nutritional deficiencies

3

1.93

    

Diphtheria

46

26.28

    

Diphtheria

90

58.06

    

Virus of poliomyelitis

1

.57

    

Virus of poliomyelitis

14

9.03

    

Undetermined cause

48

27.42

    

Undetermined cause

18

11.61

No evaluation from available data

0

0

No evaluation from available data

17

10.96


Total

175

100.00


Total

155

100.0


1These were made on 155 cases in the chain of evacuation.
Source: Johnson, J. W., Jr.: Monograph on Infectious Polyneuritis, Part II, Report to the Surgeon, MTOUSA, 1 July 1945.

Major Schoenbach and the author,22 arriving in the Mediterranean area when troop movements to the Pacific were underway, failed to find many new cases of neuropathy in visits to most of the American and British general hospitals in the theater. They therefore made a study of 70 patients with neuritis in a German prisoner-of-war base hospital in Merano, Italy. From clinical and laboratory evidence, diphtheria accounted for the majority, but a small number of the cases studied had a completely different clinical picture, the neuritis being caused by a sulfonamide, sulfamethylthiazole, used in the self-treatment of gonorrhea. Many soldiers had acquired tropical ulcers in Africa, and some of these had proved to be cutaneous diphtheria. Other types of neuritis were seen in smaller numbers. Diphtheria was observed in all its stages; indeed, the overall carrier rate of virulent micro-

22Report, Dr. George D. Gammon and Maj. E. B. Schoenbach, MC, to Surgeon, MTOUSA, 21 Aug. 1945, subject: Polyneuritis Studies in Mediterranean.


519

organisms was 17 percent throughout the hospital population. It will be recalled that a similar incidence was reported by Oppel and his associates (p. 515) among American troops in the South Pacific.

In the Mediterranean theater, the incidence of diphtheria in the Fifth U.S. Army was compared with that in the British 10 and 13 Corps and in the German Heeresgruppe C. The British incidence (expressed as monthly rates per 1,000 per annum) from September 1943 through the remainder of the year ranged from 4 to 20 and dropped to between 0.5 and 5 during 1944 and 1945. German figures during the same period were comparable but continued at 4 to 6 toward the end of the war. The American incidence was never so high but increased during the winter of 1944 to 5 per 1,000 per annum and dropped to 1 to 2 per 1,000 in early 1945. Italian civilian figures were unavailable, but it is known that Florence had severe epidemics in 1943 and 1944. In the German hospitals at Merano, the number of cases of diphtheria were as high as 34 per month. This is not surprising in view of the carrier rate (17 percent) found in the summer of 1945 in these hospitals.

The complications were noteworthy. Florentine physicians claimed an incidence of 5 to 10 percent myocarditis and of 90 to 95 percent neuritis and a mortality of about 18 percent. This extraordinary situation was suspected to be the result of poor antiserums. The Germans estimated polyneuritis as occurring in 12 percent, myocarditis in 3 percent, and death in 1 percent. These figures cannot be considered reliable and certainly underestimate the number of cases of diphtheria for, within the various armies and the civilian populations, diphtheria was rife.

Among the 70 cases of neuritis found at Merano, one group, due to diphtheria, consisted of 5 proved cutaneous cases and 21 proved pharyngeal cases followed by the complete typical neuritis with palatal accommodation and limb palsy. A second group of 14 patients had pharyngitis and typical neuritis without cultural evidence of diphtheria. A third group of two cases was similar except that a history of palatal and accommodation palsy could not be obtained, although the paralysis of extremities was identical with that found in the others. These two were classed as probable diphtheria. All three groups (42 cases) were combined and analyzed. The other types of neuritis (to be discussed) were clinically different, and in all but nine the distinction was great enough for a clear separation from diphtheritic neuritis. In these cases, along with a control group without sole throat or neuritis and with a group recovering from pharyngeal diphtheria without neuritis, cultures were made on 2 days, and the amounts of antitoxin in the serums were determined (table 98). Of the controls, approximately 17 percent had positive cultures, a figure exceeding the incidence in diphtheritic neuritis, which was approximately 12 percent. The patients with nondiphtheritic neuritis were positive in about the same percentage (18 percent) as the controls. No positive cultures were noted in the 13 cases due to sulfonamides. The amounts of circulating antitoxin did not differ significantly between the


520

groups, whether with positive or negative culture, but were higher in patients convalescent from diphtheria than in those with diphtheritic neuritis.

TABLE 98.-Clinical classification and results of cultural and serologic studies of polyneuritis, Merano, Italy, July 1945

Clinical classification

Number of cases studied

Number of cases cultured

Culture positive for virulent 
C. diphtheriae

Antitoxin content of serum

Culture negative for virulent 
C. diphtheriae, antitoxin content of serum



Number



Percent

<0.01 unit

>0.01 unit

<0.01 unit

>0.01 unit


Number

Percent

Number

Percent

Number

Percent

Number

Percent

Polyneuritis:

 

 

 

 

 

 

 

 

 

 

 

 

  

Diptheritic

42

42

5

11.9

23

54.6

19

45.4

22

59.6

15

40.4

  

Sulfonamide

13

13

0

.0

5

38.4

8

61.6

5

38.4

8

61.6

  

Postinfectious

6

6

2

 

2

 

4

 

2

 

2

 

  

Unclassified

9

9

3

 

3

 

6

 

3

 

3

 


Total

70

70

10

14.2

33

48.6

37

51.4

32

53.4

28

46.6

Control group:

 

 

 

 

 

 

 

 

 

 

 

 

  

No diphtheria, no polyneuritis

112

107

18

16.9

25

22.4

87

77.6

20

22.4

69

77.6

Convalescent diphtheria

17

17

9

52.6

5

 

12

 

1

 

7

 

More than 4 weeks after therapy

8

8

4

50.0

4

 

4

 

1

 

3

 


These studies reflect Bronson's difficulty in establishing a retrospective diagnosis of diphtheria. Nevertheless, the neuritis of diphtheria is so characteristic that the author believes it can be diagnosed on clinical grounds with considerable assurance. By 1944, it had thus become evident that diphtheria was a major cause of neuritis in all theaters of operations. In the regions where factors conducive to ulceration of the skin prevailed, the cutaneous form of infection was most frequent; elsewhere, nasopharyngeal infection was dominant.

Part II. Description and Comparison of Syndromes

DIPHTHERITIC NEURITIS

The essential effect of diphtheria toxin on the nervous system is to produce difficulty with speech, swallowing, and sight, followed by a slow, tin-


521

gling symmetrical palsy of the limbs. The paralysis develops and clears sequentially in one place after another in a leisurely pattern over many weeks, ending finally in complete recovery. The few fatalities result from myocardial failure, respiratory paralysis, or pneumonic complications of the latter. Paralysis of accommodation is a specific feature and results from weakness of the ciliary muscle. Pupillary reactions are unaffected.

Gaskill and Korb,23 who had the exceptional opportunity to follow many patients throughout their illness, described the development of neurological changes in cutaneous diphtheria thus:

The clinical course of the neuritis proceeded in regular sequence through certain definite steps, which were in some cases partially superimposed, and in others quite separate. The steps in order of their appearance were (a) cranial nerve, (b) peripheral nerve (sensory), and (c) peripheral nerve (motor) involvement.

Gaskill and Korb noted that the cranial nerve palsies lasted from 10 to 30 days and that as these were clearing up, or after an interval of a week or 10 days, the patient would then notice numbness and tingling of the hands and the feet, and in a short time objective sensory loss could be found. Motor paralysis did not appear until the end of the sensory involvement or after a latent period of 1 to 4 weeks. The motor phase lasted from 6 to 12 weeks. The average case lasted about 100 days.

Onset and Duration of Neuropathic Involvement

The evolution of neurological involvement and the structures affected in cutaneous and pharyngeal infections were somewhat different. Walshe,24 in World War I, described a local paralysis related to the site of the ulcers; he considered palatal paralysis an example of local paralysis in pharyngeal infections. Gaskill and others, however, in their cases did not observe this local paralysis in cutaneous diphtheria and noted a longer interval before the onset of the neuritis than in pharyngeal diphtheria. Liebow and his associates (p. 515) observed neuritis from 2 to 7 months after the appearance of cutaneous lesions. It is quite possible that the ulcers might have become infected with C. diphtheriae secondarily at any time in their course, but these workers described two patients from whom virulent C. diphtheriae were cultured from cutaneous lesions 2 and 4 months before the onset of the neuritis. In Gaskill's patients, the onset of neuritis was quicker and averaged 70 days after the ulcers developed, with a range of 23 to 158 days.

In patients with pharyngeal diphtheria, the interval was somewhat shorter although there was much variation. Thus, Perkins and Laufer (p. 515), in 16 patients with faucial diphtheria and in 5 patients with cutaneous ulcers, noted that in the former the interval to onset of palatal or other

23Gaskill, H. S., and Korb, M.: Occurrence of Multiple Neuritis in Cases of Cutaneous Diphtheria. Arch. Neurol. & Psychiat. 55: 559-572, June 1946.
24Walshe, F. M. R.: Pathogenesis of Diphtheritic Paralyses. Quart. J. Med. 11: 191, April 1918; 12: 14, October 1918: 12: 32, January 1919.


522

cranial nerve palsy averaged 26 days, with a range of 14 to 41 days; the cranial nerve palsies lasted on an average of 15 days, with a range of 4 to 35 days. The sensory neuritis developed in an average of 5 weeks after sore throat, with a range of 3 to 11 weeks; it reached a maximum in 25 days, with a range of 1½ to 6½ weeks; and the time from the peak to recovery averaged 8½ weeks. Motor symptoms appeared at the same time as sensory change or a little later. In their patients with cutaneous diphtheria, the interval to onset averaged 3½ months, with a range of 2½ to 5 months.

Similar data were reported by Sampson (p. 515) in 20 patients, 10 of whom had cutaneous ulcers with the onset of neuritis from 4 to 9 weeks after the ulcers developed. Copsey (p. 515), in 17 patients, largely with pharyngeal diphtheria, found that the onset of neuritis was from 3 to 8 weeks after the appearance of sore throat. In Gammon and Schoenbach's 42 diphtheritic cases (p. 519), 5 of which were cutaneous, the palatal paralysis began from the 1st to the 12th week, most frequently in the 2d to 4th week (chart 5). Paralysis of accommodation appeared a little later, from the 2d to the 8th week, most frequently in the 3d to the 6th. The limbs were involved most often in the 5th and 6th weeks, with a range of 2 to 13 weeks (chart 6). (See also table 99 and chart 7.) The neuritis of the extremities reached a maximum in 1 to 20 weeks. Improvement began most frequently in 6 to 8 weeks after onset, with a range of 4 to 24 weeks (chart 8); a quarter had

TABLE 99.-Week of onset of neurological involvement in 42 patients with diphtheria after pharyngitis

Percent of cases involved (cumulative)

Palate

Ciliary

Limbs

Quarter

2

3

4

Half

3

4

5

Three-quarters

4

6

6


CHART 5.-Onset and duration of paralysis, in weeks, after pharyngitis


523

CHART 6.-Onset of paralysis of the palate, of accommodation, and of the extremities, in weeks, after pharyngitis

begun to improve by 6 weeks; half by 8; and three-quarters by 12 weeks. At the time of examination, only one patient had fully recovered.

These various reports emphasized the characteristic slow evolution of the process over many months and pointed out that its duration was a measure of the severity of the disease. Regardless of the time involved, the sequential steps were maintained, although the process might reverse itself at any stage and the full picture might never develop. On the other hand, in the most seriously sick, the paralysis progressed to involve the trunk, head, and neck, leaving the patients completely helpless. In these patients, disability was of the longest duration.

Structures Involved

The incidence of palatal paralysis in pharyngeal diphtheria was from 7 to 10 times greater than that in the cutaneous form, while the incidence of paralysis of accommodation was roughly the same. (See table 100.) Ciliary palsy occurred in between a third and a half of the patients with each type of disease, whereas palatal palsy was seen in only 10 percent of patients with cutaneous diphtheria but in 70 to 100 percent of those with pharyngeal infection. It should be noted, however, that the incidence of ciliary paralysis may actually be higher than reported for it is easily overlooked by the patient.


524

TABLE 100.-Distribution of the neurological involvement in diphtheritic polyneuritis (in percentage)

Area of involvement


Author


1

2

3

4

5

6

7

8


Pharyngeal

Skin

Motor:

 

 

 

 

 

 

 

 

    

Palate

70

83

67

100

96

86

9

11

    

Accommodation

50

13

44

33

40

45

33

33

    

Esophagus

8

10

10

30

---

27

---

8

    

Pharynx

---

5

---

---

5

---

---

---

    

Larynx

---

---

9

21

---

---

---

2

    

Face

---

1

8

10

21

---

7

---

    

Squint

17

13

3

3

23

---

---

---

    

Limbs

ND

25

24

35

ND

39

100

52

Sensory:

 

 

 

 

 

 

 

 

    

Limbs

ND

---

42

35

ND

---

100

99

    

Tongue, palate

---

---

7

7

---

---

---

11

    

Face

---

---

7

7

---

---

---

---

    

Trunk

---

---

3

---

---

---

---

---

Sphincter

---

2

3

---

---

---

---

---

Respiration

3

---

4

10

---

7

---

---


Total

477

209

144

30

53

74

30

61


NOTE.-The authors presented by numerals are as follows: (1) Rolleston, J. D.: Acute Infectious Diseases. New York: Phys. & Surg. Bk. Co. 1925. (2) Muhlenkamp, P.: Uber die nervosen Komplikationen bei Diphtherie. Beobachtungen an 4,937 Diphtheriekranken (1921-1933). Klin. Wchnschr. 13: 1424-1428, 6 Oct. 1934. (3) Hertz, M., and Thygessen, P.: Nervous Complications in Diphtheritic Paralysis. Acta Psychiat. et Neurol. Supp. 44: 3-66, 1947; Acta Med. Scandinav. (Supp. 206) 130: 541-546, 1948. (4) Sedallian, P., Mounier-Kuhn, P., Girard, P. F., and Monnet, P.: Diphtheritic Paralysis Clinical and Anatomical Data. J. Med. Lyon 28: 481-496, 1947. (5) Brown, M. R.: The Mechanism Involved in Polyneuritis as Exemplified by Post-Diphtheritic Neuritis. Ann. Int. Med. 36: 786-891, 1952. (6) Behr, W.: Post Diphtheritic Paralysis. Deutsche med. Wchnschr. 62: 771, 1936. (7) Walshe, F. M. R.: Pathogenesis of Post-Diphtheritic Paralysis. Quart. J. Med. 11: 191, 1917-18; 12: 14, 1918-19. (8) Gaskill, H. S., and Korb, M.: Occurrence of Multiple Neuritis in Cases of Cutaneous Diphtheria. Arch. Neurol. & Psychiat. 55: 559-572, 1946.
Source: Gammon, G. D.: Effects of Bacterial Toxins on the Nervous System. A. Res. Nerv. & Ment. Dis., Proc. (1952) 32: 506-525, 1953, Table 60.

Its great value as a specific sign demands special inquiry. The author was surprised to learn also that patients frequently forgot they had previously suffered from a palatal palsy that had disappeared.

The muscles innervated by other cranial nerves may also be affected in diphtheria. Esophageal paralysis occurred in 10 to 30 percent; pharyngeal paralysis, in 5 percent; and laryngeal paralysis, in 10 to 20 percent. Squint occurred in 10 to 20 percent; any of the ocular muscles may be affected. Sensory symptoms of the tongue and face, usually paresthesias, may affect some 10 percent, as may palatal anesthesia. Loss of taste has been noted by Gaskill and Korb (p. 521), but facial hypalgesia rarely occurred. Facial paralysis is of special interest. Since it is a feature of the Guillain-Barré


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CHART 7.-Course of diphtheritic neuritis after pharyngitis, illustrating time of onset and duration of paralysis of palate (dotted line), of accommodation (broken line), and of limbs (solid line)

syndrome, its presence in diphtheritic neuritis sometimes led to confusion in diagnosis. Usually unilateral, it reached an incidence of 20 percent in some series, varying from 0 to 10; Walshe (p. 521) found it in 7 percent of patients with cutaneous diphtheria. Johnson (pp. 516 and 517) reported it in 14 percent of patients, occurring unilaterally in half and bilaterally in half.

In Gaskill and Korb's patients with cutaneous diphtheria, 35 percent developed palsies of cranial nerves and all had involvement of peripheral nerves. Slightly fewer began with palsies of cranial nerves; some began with both simultaneously. The onset in the cranial nerves forecast a more severe neuritis in the patients with cutaneous diphtheria in contrast to the patients with pharyngeal involvement, many of whom had signs referable to cranial nerves but never developed the symptoms affecting the limbs. It is a question whether all cases that had involvement of cranial nerves only came under Gaskill's observation. No cases of hemiplegia due to embolism from the heart were reported in these series.


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CHART 8.-Time course of diphtheritic polyneuritis of extremities; time (in weeks) after onset when maximum disability was reached and when improvement began

 

Symptoms and Signs of the Peripheral Neuropathy

A few patients with diphtheria in the first week or two of the illness, long before the ensuing neuropathic sequence, developed paresthesias in the limbs, suggesting a segmental or root arrangement. This in some involved the ulnar border of the forearms or hands; in others, there was tingling about the face and tongue. Commonly, however, symmetrical tingling paresthesias were felt in the distal parts, beginning in the fingers and hands, or toes and feet, or most often in both regions simultaneously and symmetrically on the two sides. Patients described this as "the tingles," a sense of the limb being "asleep" or numb. They seldom (in less than 10 percent of cases) spoke of pain. If present, it was described as a "pins and needles" sensation, never very severe nor necessitating analgesics. Very rarely, this mild pain replaced the tingles and rarely did paresthesias precede the weakness. At this stage of paresthesia, hyperrefiexia, often mentioned but seldom seen, occurred, as well as tenderness of muscles, especially the small muscles of the hand. Walshe (p. 521) reported that this muscular tenderness anticipated all other signs of neuritis; the author was also impressed by this finding although most of the reports quoted previously minimized it.

The paresthesias ascended in 1 to 2 weeks to the forearms and legs; only occasionally did they reach the root of the limbs. At this time, examination disclosed sensory impairment, its character differing from patient to patient and from one group to another. Loss of vibratory or positional sense has been emphasized in the past. Perkins and Laufer (p. 515) in their


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excellent report, which stressed the importance of the sensory findings, noted that the vibratory and the stereognostic senses were markedly affected; the tactile sense, moderately; and the perception of pain and temperature, only slightly. In contrast, all of Gaskill and Korb's series showed hypesthesia to pain, temperature, and light touch; only 8 patients out of 140 had a loss of vibration and sense of position, and in these alone was ataxia noted. In Gammon and Schoenbach's study (p. 518), in a series of 37 cases of nasopharyngeal diphtheria, 20 showed objective sensory involvement. Impairment of the perception of pain and of the tactile, but not of the vibratory or positional, sense was the most frequent combination (10 cases, 4 of which showed ataxia). No patient was observed with impaired vibratory and positional sense and normal tactile and pain sense. Ataxia was found eight times in 13 patients without objective impairment of sensory response to pinprick, touch, vibration, or position; 10 of these patients complained of tingling and 1 of pain.

Thus, a dissociation of sensory impairment has often been encountered, and ataxia has been observed without objective sensory loss. The lack of emphasis previously put on the sensory changes probably is due to the fact that diminution is much more frequent than complete loss. Also children, who predominate among patients reported in the literature, describe these symptoms less clearly. In distribution, these sensory changes are most often of the glove-stocking type, but many cases have shown a root or segmental or cord type. For example, Gaskill and Korb reported a loss of vibratory sense at the thoracic level; others noted a similar loss over the trunk. These data demonstrated that the process was not confined to nerve or root but involved the cord as well. In diphtheritic ulcers, the scar and a zone of 1 to 2 mm. around it are anesthetic. The paresthesia may cease in 1 to 4 weeks before weakness develops, or, more frequently, the two may overlap.

Motor signs developed with fatigability progressing to a flaccid palsy, more marked peripherally. The paralysis was usually symmetrical in onset and extent with minor differences in either. Atrophy developed if paralysis was severe. The lower limbs bore the brunt, and thigh as well as calf and foot were involved. The lower limbs were weak in twice as many cases as the upper limbs. The paralysis was much more marked than the sensory loss and at times it was complete in the extremities. In a smaller number of cases (10 percent), it involved the trunk and neck, leading to complete immobility. In such cases, loss of control of the sphincters ani sometimes occurred. In a small number of cases, there was intercostal and diaphragmatic paralysis. The degree of palsy varied enormously. Gaskill and Korb found the quadriceps and interossei especially susceptible. Loss of reflexes followed the distribution of the weakness. The ankle and knee jerks were most often affected; the biceps and triceps, less often. Loss of the abdominal reflexes was noted by Perkins and Laufer. The loss of reflexes may be permanent. Recovery in sensation preceded recovery from the weakness and both were usually


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complete; however, Copsey commented on the painfulness of the feet in reambulation, and Liebow and his associates described one patient with permanent atrophy of the deltoid with a winged scapula.

Antitoxin in Relation to Diphtheritic Neuritis and Serum Neuritis

The experience of World War II confirmed the observations found in the older literature that antitoxin given early-within the first 3 days of infection-prevents or greatly diminishes the changes of neuropathy, but is valueless after its onset. In fact, it may induce a primary serum neuritis, which may be local in the limb of injection, or may be widespread. In either case, pain and hyperpathia are prominent symptoms and are often severe. This manifestation may occur in addition to a diphtheritic neuropathy. Cases of this kind are quite unlike the usual diphtheritic neuritis, as illustrated by the following:

A man, 44 years old, with proven nasopharyngeal dipththeria was given 5,000 units of antitoxin on the sixth and seventh days of disease. Serum sickness appeared a week later, with swelling of the feet and ankles. This subsided at the end of 1 week when tingling paresthesia of the feet occurred, accompanied by severe pain and weakness in both hands and forearms. All these symptoms regressed during the next 2 weeks with complete restoration to normal at the end of this period. During the height of the process, decrease in cutaneous sensation along the ulnar border of the hands was noted; the tendon reflexes were normal.

A 36-year-old male, with unproven but clinically typical pharyngeal diphtheria, was given 18,000 units of antitoxin on the second day of disease. Typical diphtheritic neuropathy ensued, with palatal palsy in the third week, following in the fourth week by tingling and weakness of the extremities, absence of knee and ankle jerks, hypesthesia, and loss of position sense. Evidence of myocarditis appeared, and antitoxin was again given 7 weeks after the first dose, in amounts of 9,000 units daily for 4 days. Two days later, severe pain and hyperpathia (requiring morphia) occurred in the legs, and all the limbs rapidly became weaker. Decreased awareness of temperature and pain and loss of tactile and vibratory senses were noted in the legs, and the patient had little use of his upper or lower extremities.

Spinal Fluid

All the observers quoted previously noted increased amounts of protein in the spinal fluid without increase of cells in diphtheritic paralysis. This fact had not been previously emphasized in the American literature and unawareness of it led to confusion with the Guillain-Barré syndrome. Guillain had originally stated that the amounts of protein in the spinal fluid in his syndrome must be very high-from 1 to 2 percent; however, this restriction is certainly not generally admitted as essential to a diagnosis of infectious polyneuritis (p. 531), for, in fact, many cases never have such large amounts. Older accounts reported an early slight increase in cells, but this was not a feature of the cases observed in World War II. Johnson (p. 516) reviewed the European literature and observed many cases. Gaskill and


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Korb (p. 521), and Johnson as well, found that the protein increased early, within 2 weeks of the infection, and that the amount, according to Gaskill and Korb, was proportionate to the severity of the disease. Amounts as high as 400 to 500 mg. percent were found, although from 100 to 200 mg. percent or lower were more usual. The results of tests with colloidal materials were sometimes abnormal, and a midzonal curve was characteristic. In some cases, it was many weeks before the protein returned to normal; Gaskill and Korb found that, when the patients were clinically well, the spinal fluid protein had returned to normal.

Pathogenesis and Pathological Anatomy

In the author's review of the effects of bacterial toxins on the nervous system,25 the recent literature was summarized, including German reports on their experience during World War II. In all species, diphtheria toxin is a general cellular poison affecting most tissues. It seems probable that the initial lesion is biochemical and, as with tetanus toxin, is undetectable by techniques now available. The changes seen are the results of parenchymal and vascular degeneration, the complications thereof, and the secondary processes of repair. Peripheral nerves show edema of endoneural and perineural tissue and the cells of origin show a chromatolytic change. The myelin sheath and zone degenerate. Nuclei in the spinal cord and brain stem are affected as well. Muscle is damaged secondarily or primarily. Minute cerebral vascular lesions due to endarteritis or embolic lesions from the heart have been described. Death results from cardiac or respiratory failure, from membranous bronchial obstruction, atelectasis, or from toxemia.26

25Gammon, G. D.: Effects of Bacterial Toxins on Nervous System. A. Res. Nerv. & Ment. Dis., Proc. (1952) 32: 506-525, 1953. [Includes discussion by Harry M. Rose, pp. 518-519.]
26Pappenheimer's long study of the problem (see Pappenheimer, A. M., Jr.: Bacterial Toxins. Federation Proc. 6: 479-484, June 1947) has led him to suggest that the toxin is the protein moiety of the cytochrome B enzyme of C. diphtheriae and that its effect may result from interference with the synthesis or activity of this or related enzymes of the host. Direct proof, however, is lacking, as he found no action of the toxin in vitro or in vivo on preparations of cytochrome B. Indirect support, however, is given in the observation that, in the silkworm pupa, segmental muscle, containing the enzyme, is poisoned by the toxin, whereas cardiac muscle, lacking it, escapes. Ludwig has recently provided the first evidence of action of the toxin in vitro on the succinic dehydrogenase system; however, he attributed the effect to porphyrin present in the crude toxin. (Ludwig, G. D.: The Inhibition of the Succinic Oxidase System by Coproporphyrin. Proceedings of Physiological Society, Philadelphia, 17 Nov. 1953. Am. J.M. Sc. 227: 358-359, 1954.) It should be noted that cytochrome enzymes are all but universally distributed, and therefore interference with their action would be general, as is the case with this toxin. In poisoned skeletal muscle, phosphocreatine falls and inorganic phosphorus rises while adenosine triphosphate remains constant.
Wildführ has reported that the toxin can be found in the blood of patients a week or two before the onset of neuritis and in the spinal fluid of paralyzed patients. (Wildführ, G.: Uber Diphtherietoxingehalt im Patientenblut und Liquor bei Diphtherie-Spathlahmungen. Zentralbl. f. Bakt. (Abt. 1) 154: 18-26, 15 May 1949.) Presumably, therefore, all tissues are exposed and the susceptible ones poisoned. As yet, however, the manner of action of the toxin at a metabolic level is not clear. Rose, in commenting on Gammon's review (see footnote 25, above), pointed out that there is no actual proof that the toxin has a direct effect on the nervous system and the fact that the neuritis occurs so late raises the question whether one mode of action may not be the consequence of some type of antigen-antibody reaction. If this be so, an intrinsic antibody must be responsible, for many of these had no detectable antitoxin, and no increase in antibody was detected in serum or by Schick test in patients with diphtheritic neuritis. Furthermore, it is recognized that antitoxin can initiate a reaction, of one type at least, that is clearly different clinically from diphtheritic neuritis (p. 535).


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There can be no doubt that diphtheria toxin has its own uniquely selective action on ciliary and on sensory and motor nerves quite unlike the equally unique effects of botulinus or tetanus toxins. It seems likely that investigation of its characteristic modes of action at metabolic levels will yield information concerning the makeup of the tissues that are specifically affected by these agents to produce specific clinical syndromes.

Diagnostic Proof of Diphtheritic Neuritis

If infection with C. diphtheriae, whether of nose, throat, skin, or elsewhere, is proved by isolation of virulent micro-organisms from the infected tissue, the subsequent neuritis, which has a characteristic clinical course, can with certainty be attributed to the original infection. The chances of recovering the micro-organism depend in part on whether it is suspected and sought in lesions, many of which do not at all resemble membranous sore throat nor fit other textbook descriptions. Furthermore, if the micro-organism is not sought early, it may have disappeared by the time of the onset of neuritis. By then, the frequency of recovery of organism approaches the rate in the general population of the carriers who are spreading the infections. Thus, 3 weeks after faucial diphtheria, the rate of recovery of organisms approximates 30 percent, and it falls off rapidly thereafter.

If recovery of the micro-organism fails, the next question is whether the amounts of circulating antitoxin found are of sufficient magnitude to prove infection. The Schick test is of no help, as many of the reports that have been quoted showed; at the time of the neuritis, patients with positive and negative Schick reactions were of about equal frequency. Determinations of two levels of antibody by Bronson (p. 514) failed to demonstrate any difference between the patients and their controls. Gammon and Schoenbach's data (p. 519) showed that patients convalescent from faucial diphtheria with neuritis had antibody levels lower than in those convalescent from diphtheria without neuritis or in controls. Furthermore, a lower carrier rate (12 percent) was found in the first group than in the control population (17 percent in patients with neither sore throat nor neuritis; 18 percent in patients with nondiphtheritic neuritis). Mueller (quoted by McGuinness, p. 513) has pointed out that the clinician must decide if the presence of the micro-organism indicates the disease or the carrier state. Thus, neither the amounts of antibody found nor the results of nasopharyngeal cultures could be used to prove the presence of past diphtheritic infection nor present diphtheritic neuritis. It is obvious therefore that the diagnosis must be made early. The only alternative as far as can be seen is discovering the toxin itself in blood or spinal fluid, as has been reported by Wildführ27 but, so far as the author is aware, has not been confirmed.

27See footnote 26, p. 529.


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Actual proof of the diphtheritic origin of the neuritis is therefore often difficult and may be impossible. Nevertheless, the diagnosis can be made with some confidence on the basis of the clinical evolution. For the reasons given, the author does not agree with statements that, lacking the typical cranial nerve palsies, diphtheritic neuritis cannot be distinguished from infectious polyneuritis of the Guillain-Barré type.

INFECTIOUS POLYNEURITIS:
THE GUILLAIN-BARRÈ SYNDROME

Confusion in diagnosis, as has been noted, arose principally over the distinction between diphtheritic neuropathy and the Guillain-Barré syndrome through the unwarranted emphasis on the albuminocytologic dissociation in the spinal fluid in the latter, and the difficulty of proving diphtheritic infection. There has, in fact, been some argument about the extent of the clinical range of the Guillain-Barré syndrome and whether it represents a disease, as Guillain contended, or a group of conditions. Americans have frequently considered the albuminocytologic dissociation as diagnostic of "the syndrome," but the English school of neurologists have considered increase of the protein in the spinal fluid indicative rather of the severity than of the type of neuropathy. The albuminocytologic dissociation may, in fact, occur in poliomyelitis; in mumps meningoencephalitis; in diabetic neuropathy; occasionally in alcoholic neuropathy; with compression of spinal cord; with brain tumor, especially posterior fossa tumors; in arachnoiditis; in meningeal carcinomatosis; in syphilis; in lead encephalopathy; possibly in sandfly fever; and in other conditions.

There is no doubt, however, that there does exist a group of cases fitting Guillain's criteria and showing a combination of facial diplegia, peripheral neuropathy, and increased amounts of protein without cellular increase in the spinal fluid. Typically, the onset in such cases is abrupt, and accompanied by pain, and the peak is reached within a short time-usually a week or 10 days; the prognosis for recovery is favorable if the acute phase is successfully passed. These patients often have a preceding pharyngeal, respiratory, or gastrointestinal illness which seldom causes much complaint, and the neurological symptoms appear, as in diphtheria, with little or no evidence of infection at the time. Around this basic syndrome, there are many variations. In some cases, the neuropathy develops more slowly over a period of weeks, frequently without any pain or paresthesia. Cranial nerves other than the facial may be involved, with or without peripheral neuritis. The motor findings frequently overshadow the sensory, and the weakness may be more proximal than distal. Paralysis of accommodation or pharyngeal paralysis is seldom reported. The cause of the polyneuritis is unknown, and the diagnosis rests on the clinical picture and examination of the spinal fluid.


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Diagnostic uncertainties plagued medical officers in the Mediterranean theater where typical examples of the Guillain-Barré syndrome were unquestionably seen among the more numerous cases of diphtheritic neuritis. Johnson's final analysis of 155 cases (p. 517), however, showed that, although there were 73 diagnoses (approximately 42 percent) of the Guillain-Barré syndrome, this syndrome existed in only 10 patients (6 percent). These 10 patients showed the typical facial diplegia, but there were others that did not, only the limbs being affected. In certain patients, the course was that of an acute ascending paralysis of the Landry type, as in Johnson's Case 90, described as follows:

In this patient, a transient diarrhea was followed in 3 days by pains in the lower back and buttocks and down the back of the thighs and legs; 2 days later, severe weakness suddenly developed in the lower extremities and then in the hands. All deep tendon reflexes were absent. Sensation was intact, except for a slight decrease in vibratory sense, and cranial nerve function was normal. In the next 2 days, the trunk muscles were involved and the patient died with pneumonia 2 weeks after the onset of the diarrhea. Autopsy showed pulmonary atelectasis with bronchopneumonia. The spinal roots showed a primary inflammatory reaction with secondary degeneration of the anterior horn cells and patchy demyelinization of the roots. The spinal fluid protein measured 113 mg. percent.

A study of the cases reported in the war reveals that a rather small number were due to infectious polyneuritis of the type described by Guillain, Barré, and Strohl. The author agrees with Guillain that the clinical picture and course of disease distinguishes these cases from diphtheritic neuritis even if the latter shows bilateral facial involvement. It is important to make this distinction in order that such cases may be studied for causative agents. To combine all patients with peripheral neuritis on the basis of elevated protein without cellular increase in the spinal fluid would hinder such inquiry. We have already seen how it delayed the recognition of cases of diphtheritic origin. This view is discussed by Delp and his associates.28

POSTINFECTION NEURITIDES

With malarial fever.-Harvey and his coworkers (p. 516) described a series of 16 cases with neurological manifestations associated with recurrent attacks of malarial fever as follows: "The typical clinical picture was one in which 'irritative' phenomena were present, with sharp or stinging pain in the distribution of a peripheral nerve, followed by an * * * actual muscle contraction, intense hyperalgesia, and increased sweating." In the milder cases, numbness and tingling occurred. The symptoms were always increased with recurrence of the malaria. The nerves or roots were involved symmetrically, alone or in combinations in the lower thoracic, the trigeminal, or the sciatic regions. The axillary nerves as well as others

28Delp, M. H., Sutherland, G. F., and Hashinger, E. H.: Post-Diphtheritic Polyneuritis; Report of 5 Cases With Albuminocytologic Dissociation Simulating Guillain-Barré Syndrome. Ann. Int. Med. 24: 618-628, April 1946.


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of the upper extremities were also at times affected. During the acute attacks, the muscles of the limbs were usually flexed at the forearms and wrists, and attempts to straighten them greatly increased the pain. The hyperalgesia lasted several weeks. Occasionally, hypalgesia and hypesthesia were noted. It was suggested that the symptoms might be attributed to vascular lesions of the nerves. Plasmodium vivax was the common type of the associated infection, although mixed infections were suspected in some cases. Some 18 of 100 relapsing cases of malaria showed a milder form of the disability.

After other severe infections-Neuropathy has also been described with severe sepsis, whatever the cause, as well as with diphtheria and other specific infections, such as the cases attributed to malaria by Harvey, and those ascribed by Wilke to dysentery in German patients following Shiga infections (noted by Johnson). These last had an albuminocytologic dissociation in the spinal fluid.

Neuropathy following pneumonia is illustrated by the course of disease in a 37-year-old man who had tropical ulcers of the legs, from August to October. On 23 March, bilateral bronchopneumonia developed, which was treated with a sulfonamide eubasin. About a month later, after the patient had improved but was still febrile, he awoke to discover weakness in the legs, hands, and fingers. There were no pains or paresthesias. The weakness increased for 3 weeks and he could barely walk. The small muscles of the hands and legs were wasted and the quadriceps were weak. The patient was ataxic and had a sensory loss of the glove-stocking type for pain, temperature, and touch. Position and vibratory senses were normal and the cranial nerves were normal. The process was symmetrical. The ankle and knee tendon reflexes were absent, but the biceps and triceps were normal.

In four other cases, septic wounds led to delirium and other signs of toxic psychosis and to a neuritis identical in course with the postdiphtheritic cases except for the lack of palatal or other cranial nerve involvement, symptoms of which, however, might have been undetected. Only one of the whole group of six patients had a slightly elevated cerebrospinal fluid protein (67 mg. percent). Diphtheria could not be ruled out in these cases, but similar ones have been noted in civil life where diphtheria was not a factor.

In a patient reported by Zimmerman and Lowry,29 infectious hepatitis was followed by a typical motor and sensory polyneuropathy of the Guillain-Barré type, with unilateral involvement of facial nerve. The condition progressed for 17 days and then improved to the point of complete recovery in 4 months. The protein in the spinal fluid measured 192 mg. percent.

29Zimmerman, H. J., and Lowry, C. P.: Encephalomyeloradiculitis (Guillain-Barré Syndrome) as a Complication of Infectious Hepatitis--Case Report. [Professional paper.]


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PERIPHERAL NEUROPATHY, MOSTLY PERONEAL AND AXILLARY, 
CAUSE UNKNOWN

Harvey, Kuffler, and Tredway (p. 516) described 20 cases of peripheral neuropathy, mostly peroneal and axillary, cause unknown. These cases were said to resemble the group described by Spillane30 and were clearly distinguishable from the cases associated with recurrent malaria (p. 532). The authors described the conditions as characterized by the sudden onset of motor and sensory involvement, usually of a single nerve. Function, in most cases, returned within 4 to 6 months. In 15 cases, the common peroneal nerve was attacked; in 3, the axillary nerve; and in 1, the radial. Typically, the patient awakened to find weakness; this reached a peak within 1 to 3 days. About a quarter of the patients complained of pain, which was especially sharp and burning in the axillary type. This feature was emphasized by Spillane in a study of 46 patients, most of whom had served in the British MEF (Middle East Forces). Some patients had "pins and needles" paresthesias lasting from a few days to a few weeks. Sensory loss over the dorsum of the foot or lateral surface of the leg was noted in over half of the patients with peroneal involvement; the affected area was surrounded by a zone of intense hyperesthesia. In the patients with axillary involvement, sometimes other branches of the brachial plexus were affected. Spillane described pain in the chest wall. Electromyography was used to trace the degree of involvement and recovery. Two of the patients with axillary neuritis showed atrophy with no recovery in 6 months. The author has seen similar patients without recovery in over a year, and similar cases occurred among those described by Johnson in the Mediterranean theater. One of the patients with peroneal involvement relapsed without known cause after 3 months of improvement. The spinal fluid, when examined, was found normal.

Harvey considered this group distinct from a third group with polyneuritis accompanied by high protein in the spinal fluid without increase in cells, although he did not describe these last in detail. Atabrine (quinacrine hydrochloride) or quinine could not be implicated, and recurrent malaria did not affect these patients. Pressure appeared to play no role in the cause although the radial and peroneal nerves were notably susceptible. Harvey called attention to civilian cases in London reported by Mason31 and to cases noted in Malta by MacPherson and Clark (1943). Weinstein and Gersten (p. 517), and Weinstein32 alone, described patients with shoulder-girdle palsy resembling Harvey's cases and attributed them to vaccina

30Spillane, J. D.: Localized Neuritis of Shoulder Girdle; Report of 46 Cases in MEF. Lancet 2: 532-535, 30 Oct. 1943.
31Mason, R. W.: Brachial Neuritis Occurring in Epidemic Form. Lancet 2: 662-663, 29 Nov. 1941.
32Weinstein, E. A.: Delayed Appearance of Peripheral Neuropathy Following Serum and Vaccine Injection. [Professional paper.]


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tion. An outbreak of peroneal palsy33 occurred in 41 persons in a German prisoner-of-war camp at Alva, Okla., which bore some clinical resemblance to the disease described by Harvey; that is, one or both peroneal nerves and occasionally tibial nerves were affected by tingling parethesias and foot drop suddenly ensued. Occasionally, the fingers tingled. A blunting of sensation and decrease in ankle jerks and tone were noted. Improvement occurred in most instances. It is difficult to decide if these cases form a unity, and it is possible that the shoulder-girdle group differs from the peroneal type. Weinstein's suggestion that vaccination was the cause has not been widely accepted.

POSTVACCINATION NEURITIS

Postvaccination neuritis was observed by Sabin34 in rare cases after immunization against Japanese B encephalitis. It was usually a segmental motor and sensory paralysis in the injected limb, or a complication of serum sickness. Note has been made of an allergic reaction to diphtheria antitoxin presenting as a local or general manifestation (p. 528).

The cases reported by Weinstein and Gersten were predominantly of the shoulder-girdle type. Thirteen cases seen in North Africa from July 1943 to January 1944 were reported. Later, Weinstein added six more cases and suggested that the cause was due to prior injections. He described the syndrome as "characterized by a rapid, often painless onset of motor involvement with frequently enduring paralysis and atrophy of the affected muscles, and a tendency for limitation to a single extremity with a predilection for the shoulder girdle." In most instances, there was multiple but local nerve involvement, which in some cases was asymmetrically bilateral. The onset was always rapid and at times sudden, the victim awakening to find paralysis of arm or shoulder. A sensation of numbness or deadness was frequent, but actual pain was present in only 7 of the 19 cases and was severe and persistent in only 2, each with involvement of the axillary nerve. In 16 cases, an upper extremity was affected, and in 4 patients both arms were involved asymmetrically. The brunt of the paralysis fell upon the shoulder girdle, usually with multiple neurological involvement. The following nerves were affected: Axillary, 6; long thoracic, 6; thoracodorsal, dorsoscapular, suprascapular, and radial, each 4; and musculocutaneous ulnar and spinal accessory, each 2. Isolated unilateral common peroneal palsy was noted twice. Sensory impairment was less conspicuous than palsy and was found chiefly in lesions of the axillary and radial nerves, confined

33Report, Maj. Frank Kaminsky, MC, and Capt. Max E. Johnson, MC, to Medical Director, Eighth Service Command, Army Service Forces, Dallas, Tex., 26 Sept. 1945, subject: Investigation at Prisoner-of-War Camp, Alva, Okla.
34Sabin, A. B.: Epidemic Encephalitis in Military Personnel; Isolation of Japanese B Virus on Okinawa in 1945, Serologic Diagnosis, Clinical Manifestations, Epidemiologic Aspects and Use of Mouse Brain Vaccine. J.A.M.A. 133: 281-293, 1 Feb. 1947.


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to the isolated sensory supply of the nerves involved. Palsy was maximal at onset and not progressive. Recovery was noted in about half the cases within 2 to 3 weeks, but the others remained paralyzed and atrophy ensued without fasciculations. The spinal fluids were normal.

Considering various possible causes, Weinstein commented on the absence of prior or current infection, although the late stage resembled poliomyelitis. No toxic agents, including sulfonamides, were implicated, and there was no suggestion that pressure had been operative. The only common factor was prior injection of vaccine, toxoid, or serum, which had been given to each of this group within 2 weeks to 3 months. None had serum sickness. For this reason and because the type of involvement resembled that of postvaccination neuropathy, Weinstein attributed the cases to this cause. He placed the incidence second to postdiphtheritic neuropathy. There is no doubt that postvaccination neuropathy occurs without serum sickness. The interval is longer after injection in Weinstein's cases than that usually recognized. Spillane (p. 534) did not associate his similar cases with this cause. Localization of poliomyelitis to an injected area has been noted. In most descriptions of postvaccination neuropathy, pain is however a prominent feature. It would thus appear that Weinstein's suggestion, while a valuable one, requires verification.

NEURITIDES CAUSED BY TOXIC AGENTS

After sulfamethylthiazole in gonorrhea-Sulfamethylthiazole, which had been rejected in the United States when it was found to produce "anterior horn cell disease," was purchased surreptitiously in Italian pharmacies by German soldiers for the self-treatment of gonorrhea. It proved highly active for it "cured the gleet and dropped the feet."

Gammon and Schoenbach studied 13 patients in whom the onset was abrupt, with more or less severe pain in the legs and feet, followed in 1 to 7 days by the sudden onset of weakness. The maximum involvement was reached at the earliest in a week and in the other cases a few days later. All patients were paralyzed below the knees and in half of them the hands were also involved, usually at the same time or shortly thereafter. Here, the weakness was highly selective. The muscles of the thenar eminence, especially the short flexor of the thumb, were affected, and occasionally the weakness spread to the first and second interosseous muscles. The paralysis was flaccid and followed by atrophy and cessation of pain. The ankle jerks were lost, but the knee jerks and the triceps and biceps reflexes were unaffected. Sphincters were also unaffected. Only 2 of the 13 patients showed a slightly impaired sensory response to pinprick and light touch below the knees. The process was essentially a selective symmetrical paralysis with painful onset. Improvement was slow and incomplete with atrophy a permanent residuum in some cases, and only half the patients had shown any


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improvement when examined. This began in the first to fifth months after onset. Two patients had a relapse, one after a second course of sulfonamide and the other after treatment with olobintin, a derivative of turpentine. The spinal fluid protein in these cases was not increased.

An interesting feature was the delayed onset of the palsy, which according to the German physicians might be several weeks after stopping the medicine. They also stated they had encountered the condition only during the treatment of gonorrhea and no other diseases. The condition resembled the neuropathy after Uleron, a disulfanilamide, and the triorthocresol "jake" paralysis. The symmetrical involvement distinguished these cases from the group studied by Harvey and his coworkers and by Spillane.

Trinitrotoluene toxicity.-Neuritis in munition manufacturers was reported in World War I. At the request of Dr. L. C. McGee, medical director of the Hercules Powder Company, the author, with Army ordnance and U.S. Public Health Service officials, saw eight patients suspected of this condition in a plant at Chattanooga, Tenn. Some of them showed an obviously hysterical sensory loss in the limbs and a few had tingling paresthesias of the limbs lasting several months. Sensory tests suggested an impairment of pain and temperature sense in a glove-stocking distribution, occasionally sparing the palms and soles. The motor weakness of which some complained was largely subjective. Tendon reflexes were unaltered. Cranial nerves were unaffected. The spinal fluid was not examined. The subjective nature of most of the complaints quite naturally led to conflicting interpretations of the evidence and prompted the question whether any disease at all was present. Physicians in the community had not observed similar cases in their practice. A sample survey of other plants by the U.S. Public Health Service failed to turn up other examples, a tribute to the effectiveness of industrial control methods for handling this undoubtedly toxic substance.

STARVATION NEURITIDES

This subject is discussed by Pollack (ch. X) and by Youmans35 and is referred to only briefly here. Three principal syndromes were encountered-classical beriberi, burning feet, and the involvement of optic and auditory nerves with degeneration of spinal cord in lateral and posterior columns. Long-term followup studies have shown that recovery was often incom-

35Youmans, John B.: Malnutrition and Deficiency Diseases. In Medical Department, United States Army. Preventive Medicine in World War II. Volume III. Personal Health Measures and Immunization. Washington: U.S. Government Printing Office, 1955, pp. 159-170.


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plete.36 Similar British experience was summarized by Denny-Brown.37 These neurological manifestations arose chiefly in prisoners, particularly in the Eastern theaters of war. Malnutrition as a cause of neuritis outside the prisons was unusual unless accompanied by other diseases, such as dysentery, and accordingly did not often present a diagnostic problem.

SPECIAL PROBLEMS IN DIFFERENTIAL DIAGNOSIS

Hysteria-Hysteria, as well as other diseases of the nervous system, had to be distinguished in patients with neuropathy, just as the various types of neuropathy had to be distinguished from each other. Hysterical paralysis was frequently suspected until clear evidence of organic disease was uncovered. Findings indicative of toxic myocarditis and the discovery of elevated amounts of protein in the spinal fluid frequently clarified the diagnosis as did also the gradually growing acquaintance with the various syndromes.

Poliomyelitis.-Frequently, poliomyelitis had to be considered because, as a result of the transfers through various installations out of combat areas, adequate study was made late, at a time when the cells in the spinal fluid had diminished and the protein was still elevated. It is known that this rises several weeks after infection and may remain elevated for months. The pharyngitis or gastroenteritis of poliomyelitis is followed in a few days by paralysis, which reaches its peak in a few days at most. The onset may be painful, but sensory loss is not found with the exception of the rare case of transverse myelitis presenting a sensory level. The older clinical suspicion that poliomyelitis could cause such a condition has now been confirmed by means of the newer diagnostic tests. The Landry type of poliomyelitis ending fatally could not be distinguished from that of other causes unless there was sensory impairment. Bulbar poliomyelitis also proved difficult to distinguish from the Guillain-Barré syndrome. As a rule, however, the asymmetrical and patchy distribution of paralysis and atrophy permitted the differentiation from neuropathy.

Infectious mononucleosis.-This occasionally involves the nervous system and one form resembles the Guillain-Barré syndrome. Ricker, Blumberg, Peters, and Widerman38 reported two fatal cases, with post mortem study at the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C. These patients had a febrile illness with

36Report, prepared by the Department of Health, Education, and Welfare in cooperation with the Veterans' Administration, Department of Labor, and Department of Defense Pursuant to Public Law 744, 83d Congress, 2d Session, subject: Effects of Malnutrition and Other Hardships on the Mortality and Morbidity of Former U.S. Prisoners of War and Civilian Internees of World War II: An Appraisal of Current Information.
37Denny-Brown, D.: Neurological Conditions Resulting From Prolonged and Severe Dietary Restriction (Case Reports in Prisoner-of-War, and General Review). Medicine 26: 41-113, February 1947.
38Ricker, W., Blumberg, A., Peters, C. H., and Widerman, A.: Association of Guillain-Barré Syndrome With Infectious Mononucleosis, With Report of 2 Fatal Cases. Blood 2: 217-226, May 1947.


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signs of rapidly advancing flaccid weakness of limbs, trunk, pharynx, and face with minor sensory impairment of a glove-stocking type. Death occurred from respiratory failure and atelectasis with pneumonia. Specimens of spinal fluid showed a modest pleocytosis and elevation of protein. Pathologically, the process was a widespread acute neuromeningomyeloencephalitis. Inoculation of specimens of the brain and of the spinal cord from one patient into mice and guinea pigs caused no disease. The authors pointed out that certain patients with peripheral paralysis have, unlike those with poliomyelitis, a good prospect for recovery.

Mumps.-Mumps meningoencephalitis with neuropathy was reported by Gellis, McGuinness, and Peters39 in an outbreak in Army troops.

Compression.-Compression from tumors or herniated disks with Froin's syndrome in the spinal fluid gave rise to some confusion until collateral evidence of cord disease developed. Unrecognized shell fragments in the brachial plexus or compression by cervical rib, scalenus anticus muscle, or traction, or pressure from various sources were rare causes of confusion.

Alcoholic neuropathy-This was not often a diagnostic problem. Alcoholic neuropathy evolves acutely with a good deal of pain and can be readily recognized.

Tabes dorsalis-Tabes dorsalis was easily distinguished by serological and spinal fluid studies as well as by the slow course.

Sandfly fever-This fever entered the diagnostic picture in Italy, owing to the aches in the limbs and the changes in the spinal fluid that were occasionally found. In such cases, there was usually a lymphocytic pleocytosis as well as a rise in the protein. Paralysis was not noted. A somewhat similar picture was seen in a group of German prisoners with quintana or Volhynia fever (trench fever). This entity has not been encountered since World War I. The dramatic fever curve with a rise every 5 days for five or six episodes disclosed the diagnosis.

Beriberi neuropathy.-This was a differential problem in only a comparatively few instances involving prisoners or in association with other disease, particularly in the Far East.

One of the chief difficulties arose when multiple possible causes existed in the same person, such as malnutrition, in an area where diphtheria was endemic. It was not always possible to separate the influence of each, or the combined effect of all.

CONCLUSION

Two entities could be separated on the basis of their distinctive clinical course. One was found in groups of patients with shoulder-girdle or peroneal

39Gellis, S. S., McGuinness, A. C., and Peters, M.: A Study on the Prevention of Mumps Orchitis by Gamma Globulin. Am. J.M. Sc. 210: 661-664, November 1945.


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palsy reported by Harvey and his coworkers and by Spillane. The protein in the spinal fluid was said to be normal in amount. The process was asymmetrical and frequently led to permanent atrophy. The other entity was the condition described by Harvey with severe pain and cramping phenomena in association with relapsing malaria.

The chief diagnostic problem was posed by the Guillain-Barré syndrome in relation to diphtheritic neuritis. Proof of prior infection with diphtheria frequently could not be reliably demonstrated by recovery of the microorganisms, by the Schick test, or by the amounts of serum antibody. Diagnosis was made more difficult by the fact that the pharyngeal infection need not be present since extrafaucial sites may exist, and the laboratory methods require great skill and experience. The Guillain-Barré syndrome, on the other hand, may occur in association with diphtheria, malaria, poliomyelitis, and other infections. Its presence did not constitute a definitive diagnosis in itself, nor is it constantly characteristic of any of these conditions, except infectious polyneuritis of unknown cause, and diphtheritic neuritis.

The diagnosis in the end rests on the clinical considerations. In both diphtheritic neuritis and the Guillain-Barré syndrome, the same region may be attacked. Thus, facial diplegia may occur in diphtheritic neuropathy and pharyngeal paralysis with the Guillain-Barré syndrome. But the incidence of the facial diplegia is very much higher in the latter condition and pharyngeal paralysis in the former. Ciliary palsy is considered specific for diphtheria, but it is discovered in only a third of the cases. Furthermore, it has been claimed that it may be found in the Guillain-Barré syndrome, though this is open to question.

There are, however, differences between the two which characterize the bulk of the cases. In diphtheritic neuritis, the course slowly evolves over weeks to reach its peak, while infectious polyneuritis is abrupt and quick in reaching its maximum. Pain is more typical of the latter and tingling paresthesias of the former. Based on these criteria, there are two typical syndromes that can be readily and reliably distinguished. Even lacking a history of the early cranial nerve palsies of diphtheria, the later tingling paresthesias followed by paralysis can be recognized. Although in the majority of cases the condition can be identified by the differences in the time of evolution, variations may be encountered in any toxemia, depending on the dose of the causative agent. Thus, Johnson reported a few cases with abrupt onset of paralysis of the limbs in diphtheria; but this is a great rarity. On the other hand, there are undoubtedly cases of polyneuritis with facial diplegia with slow subacute development over weeks; many of these patients have no paresthesias or pain while the paralysis is increasing. Such cases are customarily classified with the Guillain-Barré syndrome. Again, there are cases with abrupt onset of multiple neuritis of the limbs without facial involvement; these may be distinct or a variant of the Guillain-Barré


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syndrome. Other cases with signs referable to cranial nerves but without involvement of limbs have also been grouped with it.

These clinical distinctions must accordingly be maintained until the various causative agents can be defined, when a reclassification can be made that embraces the full range of the clinical picture. If this is not done, there is danger that a specific causative agent may be mistakenly believed to be operative in producing the group as a whole. Thus, if viral studies were done in a case of unrecognized diphtheritic neuropathy, the erroneous conclusion might be reached that a virus was not responsible for any of the conditions falling in the wide spectrum of the whole group, while actually unrecognized viral disease might account for some of them.

In patients with diphtheria, antitoxin is not indicated after neuropathy has developed for it does no good and may add an allergic neuropathy to the other. Rest in bed in the presence of myocarditis must be enforced to avoid a fatal outcome. In patients with respiratory paralysis or pharyngeal-laryngeal paralysis, due to any cause, prevention of pneumonia is an equally serious problem. In the main, rest until beginning improvement is essential, along with general measures of physiotherapy and adequate diet. Supplementary vitamins apparently do not influence the course of disease.

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