CHAPTER XIX
Peripheral Neuritis
George D. Gammon, M.D.
The incidence of neuritis in World War II was not high, andthe condition, statistically at least, was of relatively minor concern among themedical and surgical problems of the Army. Practically, its importance arosechiefly from the severity of the invalidism it produced. Several new types wererecognized, but no new causative agents were discovered. Ultimately, the greaternumber of cases were recognized as being due to diphtheria. This recognition wasdue to the growing familiarity with clinical manifestations, to the improvementin confirmatory diagnostic tests, and to the rising incidence of diphtheriatoward the end of the war, particularly in Europe. Experience brought, too, awider realization that an albuminocytologic dissociation in the spinal fluidcould occur in a wide variety of neuritides and that this dissociation, ofitself, did not establish a diagnosis of infectious polyneuritis of theGuillain-Barr? type.
The first part of this chapter is an account of the problemsas they appeared in the various theaters during the course of the war; thesecond part is an attempt to characterize the various syndromes and to emphasizethe difference between them, in the conviction that clinical distinctions arethemselves of value and must be maintained when causative agents cannot bedefined.
Part I. Clinical Experience
Observations made early in World War II, cited by McGuinness,1indicated that from 10 to 76 percent of American servicemen weresusceptible to diphtheria, depending on their prior residence. Since it wasknown that they would enter foreign areas in which the disease was endemic, thereports of cases in U.S. troops from the Pacific areas and the China-Burma-Indiaand Mediterranean theaters were not unexpected. In these regions, however, theproblem of proving a suspected diagnosis was fraught with difficulties. Thedemonstration of virulent micro-organisms in lesions of the throat or the skinwas not easy, nor was the environment of forward combat areas favorable fordoing such work. In all, 5,724 cases of diphtheria, with 125 deaths, werereported 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.
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DIFFERENTIAL DIAGNOSIS
Correspondingly difficult, particularly during the earlyyears of the war, was the differential diagnosis of the nature of a neuritis. Inthe Tropics, paralysis was associated with cutaneous ulcers and with malaria,conditions generally unfamiliar to American medical officers. In Africa andItaly, the albuminocytologic dissociation was a frequent finding. Cases weresometimes ascribed to infectious polyneuritis on this basis alone until the samedissociation had been repeatedly demonstrated in proved cases of diphtheria, inlate poliomyelitis, and in other conditions, poorly defined. In some syndromes,the etiology was, and remains, obscure.
Typical diagnostic problems are illustrated in Bronson'sreport2 on two series of patients; thefirst, from the 4th General Hospital in Melbourne, Australia, in 1943, dealingwith 13 cases of neuropathy in marines who had invaded Guadalcanal, and thesecond, from Moore General Hospital, Swannanoa, N.C., in 1945, dealing with 60"similar cases" with skin diseases. The marines, without much contactwith natives or foe, had developed severe sore throat and later a polyneuritis.There was no evidence to substantiate the diagnosis of diphtheria from culturalstudies, Schick tests, or the titration of diphtheria antitoxin in their serums.Actually, the amounts of antitoxin found in the patients were identical withthose found in the control cases. Attempts to isolate viruses were likewiseunsuccessful, and pooled nasopharyngeal washings inoculated into embryonatedeggs, spinal fluid inoculated intracerebrally into mice, and stools inoculatedintraperitoneally into monkeys failed to provoke disease. The onset of theneuropathy 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 7months).
In Bronson's second series of 60 "similar cases"with skin diseases studied in 1945, diphtheria was proved in 7 and suspected in5; no evidence was produced to suggest that the other 48 cases were caused bydiphtheria. The neuropathy was slow in developing and in subsiding to a completerecovery and was accompanied by increased amounts of protein in the spinalfluid. Although admitting that these findings were not consistent with thepicture of diphtheritic neuropathy, Bronson concluded that they were, in fact,unrelated to diphtheria. Weighing against this view was the evidence that othermarines fighting alongside the troops originally studied by Bronson, andevacuated to a naval hospital ship, were proved to have diphtheria anddiphtheritic neuritis by Norris and his associates,3who identified Corynebacterium diphtheriae and who were among thefirst to recognize the character of the problem. Bronson's cases could not, inretrospect, 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.
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diagnosed, and they illustrated the difficulties in proving adiagnosis of diphtheritic neuritis.
Meanwhile Liebow, MacLean, Bumstead, and Welt4 reported oncutaneous diphtheria seen in 1943 and 1944 at the 39th General Hospital,Auckland, New Zealand, with an extensive review of the literature, and describedmany cases of neuritis. Oppel, Smith, Montanaro, and Tompsett5 of the 9thGeneral Hospital, also in the Pacific, found virulent C. diphtheriae invarious cutaneous lesions in one out of six individuals and noted that spreadoccurred from these patients regardless of isolation. They incriminated flies.These two studies, as well as others, emphasized the predominance of cutaneousover pharyngeal diphtheria. Oppel and his coworkers observed 9 cases ofneuropathy in 210 cases of diphtheritic infection, an incidence of 4 percent.
In the China-Burma-India theater, an outstanding study ofcutaneous diphtheria was made at the 20th General Hospital, Assam, India, byLivingood.6 As described in his letter of 9 October 1944 to thecommanding officer of that hospital, the ulcerous skin lesions were suspected asdiphtheritic as early as June 1944, although cultural proof was lacking. Thedevelopment of typical postdiphtheritic neuritis in one patient and the death ofanother in cardiac failure substantiated this suspicion, and confirmation bycultural studies finally came in October 1944. Livingood reported on 140 cases,61 with neuropathy. Gaskill's description7 on these neuropathic cases presenteda clear and detailed summary which showed the neuropathy to be distinctive. Inretrospect, this experience proved almost unique, since the cases were followedfrom onset to conclusion, and full advantage was taken of the opportunity tostudy and describe them (pp. 521 and 525). Many cases were also reported fromthe 69th General Hospital in this theater.8 Other excellent reportsof diphtheritic neuritis seen early in the war, in patients evacuated fromvarious theaters, were made by Perkins and Laufer9 with 21 cases, by Sampson10with 20 cases, and by Copsey11 with 17 cases.
As troops with cutaneous diphtheria appeared in hospitals ofthe United States, the factor of contagion became a matter of concern. TheCommission
4Liebow, A. A., MacLean, P. D., Bumstead, J. H.,andWelt, 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 ofDermatology and Syphilology, to Commanding Officer, 20th General Hospital, 9Oct. 1944 and 25 Jan. 1945, subject: Cutaneous Diphtheria.
7Letter, Maj. Herbert S. Gaskill, MC, Chief, NeuropsychiatricSection, 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 InternalMedicine in India-Burma Theater. [Official record.]
9Perkins, R. F., and Laufer, M. W.: Clinical Study ofPostdiphtheritic Polyneuritis. J. Nerv. & Ment. Dis. 104: 59-65, July1946.
10Sampson, J. J.: Late Neuronitis Following Proved andSuspected 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.
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on Meningococcal Meningitis, Army Epidemiological Board, froman extensive survey at Letterman and Moore General Hospitals, concluded thatdiphtheria was indeed a problem in the Pacific, that a large percentage of casesof polyneuritis in general hospitals were postdiphtheritic, and that the currentclinical classification of polyneuritis was not satisfactory.12 Meanwhile,the skepticism of physicians in the Southwest Pacific Area, based upon failureto obtain laboratory confirmation of diphtheria, was gradually yielding togrowing experience, as reported by Col. Benjamin M. Baker,13 MC, in1944. Subsequently, measures were taken that resulted in a steady decline in thenumber of cases during that year. Liebow and his associates (p. 515) noted that,after the diphtheritic nature of certain tropical ulcers became apparent, therewas not an instance of the neuritis of the type just discussed that could not berelated either to the ulcers, to sore throat, or to proved diphtheriticpharyngitis or dermatitis. They concluded that the vast majority of neuritisseen in the Tropics was diphtheritic in origin. These views were incorporated inWar Department Technical Bulletin (TB MED) 143, "CutaneousDiphtheria," February 1945.
There were other types of neuropathy in the Pacific areas,however, that did not fit into this pattern. Harvey, Kuffler, and Tredway14 reportedfrom the 118th General Hospital, Tolosa, Leyte, a group of 20 cases of unknowncause in which the manifestations were quite unlike those of diphtheriticneuritis but resembled the shoulder-girdle and peroneal paralysis described bySpillane. (See page 534.) Harvey15 also reported still another type, associatedwith attacks of malarial fever (p. 532). This was overt in 16 cases and found inmilder form in 18 of 100 consecutive cases of malaria.
Another group of 40 cases of neuropathy was reported from thePhilippines in 1945 by Pessin and Silverman.16These appear to haveshown diverse clinical manifestations and course. Over half the patients hadgastrointestinal disturbances and 40 percent had infectious hepatitis; theauthors postulated that both infection and vitamin deficiency were responsiblefor the paralysis.
Meanwhile, in Africa and Italy, the problem of neuropathypresented itself chiefly as an outbreak of what appeared to be infectiousneuritis of the Guillain-Barr? type. Maj. Joseph W. Johnson, Jr., MC, of the300th General Hospital, examined many patients, collected case records, and
12Memorandum, Commission on Meningococcal Meningitis, ArmyEpidemiological Board, for The Surgeon General (through Brig. Gen. S. Bayne-Jones, Preventive Medicine Service, Office of The Surgeon General, 6 July1945, subject: Diphtheria Infections at Letterman General Hospital, SanFrancisco, California, and at Moore General Hospital, Asheville, NorthCarolina.
13Letter, Col. Benjamin M. Baker, MC, Consultant inMedicine, to Brig. Gen. Earl Maxwell, Headquarters, U.S. Army Forces, SouthPacific Area, 16 Mar. 1944.
14Harvey, A. M., Kuffler, S. W., and Tredway, J. B.:Peripheral Neuritis; Clinical and Physiological Observations on Series of 20Cases of Unknown Etiology. Bull. Johns Hopkins Hosp. 77: 83-103, August 1945.
15Harvey, A. M.: Type of Neuritis Associated With MalarialFever. Bull. Johns Hopkins Hosp. 75: 225-231, October 1944.
16Pessin, J., and Silverman, D.: Peripheral Neuritis inthe Philippines. [Professional paper.]
517
analyzed the data, in a study that was finally embodied intwo monographs. As a result of this focusing of attention upon the subject, thelate Maj. Emanuel B. Schoenbach, MC, and the author were sent to Italy by theCommission on Neurotropic Virus Diseases of the Army Epidemiological Boardshortly after the end of the war in Europe. Almost concurrently, Lt. Col. AimsC. McGuinness, MC, and Dr. J. Howard Mueller studied diphtheria in the Europeantheater.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 theso-called Guillain-Barr? syndrome had appeared in North Africa; five cases werereported by Lt. Col. Morton H. Hand (cited by Johnson) in January 1944. Manyadditional cases were observed widely throughout the theater as summarized fromthe literature by Johnson, who reported another 15 cases of Guillain-Barr?syndrome in April and still more in June 1944. In September 1944, theGuillain-Barr? syndrome was made reportable to the Surgeon, NATOUSA (NorthAfrican Theater of Operations, U.S. Army). Weinstein and Gersten19 hadnoted another type of shoulder-peroneal palsy. Lt. Col. Theodore J. C. VonStorch (quoted by Johnson) found after extensive investigation that neuropathyaccounted for 1.5 percent of all the medical dispositions between Anzio andCasablanca in February 1944. Johnson20 presented evidence, based on 119cases of the Guillain-Barr? syndrome, indicating that the diagnoses had beenmade as a result of the finding of albuminocytologic dissociation in the spinalfluid without much, if any other, relation to the syndrome described by Guillain,Barr?, and Strohl. From his extensive data, he concluded that "a majorityof these cases seen in Italy were probably attributable to post-diphtheriticpolyneuritis (58.06 percent)." He noted "that the diagnosis ofdiphtheria is not easy, its substantiation even more difficult, and thatdiphtheria recently has been atypical." He pointed out the great difficultyof properly evaluating such cases during active combat.
Johnson made a second report,21 1 July 1945, tothe Surgeon, MTOUSA, based on restudy of the records of 155 patients, 31 percentof whom had been observed on his own service in a general hospital in thetheater. He reclassified them (table 97) on the basis of the total clinicalfindings rather than on spinal fluid or other tests and concluded that here, asin the Pacific, diphtheria accounted for the major portion of the neuritides. Itis noteworthy that, in 20 of the 90 cases with a typical diphtheria neuritis, nohistory of a
17See footnote 1, p. 513.
18Johnson, J. W., Jr.: Monograph on InfectiousPolyneuritis, Part I, Report to the Surgeon, MTOUSA, 2 Feb. 1945.
19Weinstein, E. A., and Gersten, D.: An Unusual Type ofPeripheral Neuropathy: Report of 13 Cases. M. Bull. North African Theat. Op. 1:9-10, May 1944.
20(1) Johnson, J. W., Jr.: Infectious Polyneuritis-DiagnosticCriteria 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.
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prodromal illness suggestive of diphtheria was recorded andthat in 66 percent diphtheria had not been recognized until the development ofthe complication. Johnson commented on the British cases in the theater and oncivilian cases in Italy. Of 397 patients with diphtheria in a hospital inFlorence, neural complications developed in 90 to 95 percent, but myocardialcomplications in only 5 to 10 percent. He contrasted this with the very lowincidence of neural complications (less than 1 percent) and the higher incidence(20 percent) of myocardial complications in the United States.
Original diagnosis | Number of diagnoses1 | Percent of diagnoses | Reclassification diagnosis | Number of cases | Percent of cases |
Guillain-Barr? syndrome | 73 | 41.71 | Guillain-Barr? 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 |
|
| 175 | 100.00 |
| 155 | 100.0 |
1These were made on 155 cases in the chain of evacuation.
Source: Johnson, J. W., Jr.: Monograph on InfectiousPolyneuritis, Part II, Report to the Surgeon, MTOUSA, 1 July 1945.
Major Schoenbach and the author,22 arriving in theMediterranean area when troop movements to the Pacific were underway, failed tofind many new cases of neuropathy in visits to most of the American and Britishgeneral hospitals in the theater. They therefore made a study of 70 patientswith neuritis in a German prisoner-of-war base hospital in Merano, Italy. Fromclinical and laboratory evidence, diphtheria accounted for the majority, but asmall number of the cases studied had a completely different clinicalpicture, the neuritis being caused by a sulfonamide, sulfamethylthiazole, usedin the self-treatment of gonorrhea. Many soldiers had acquired tropical ulcersin Africa, and some of these had proved to be cutaneous diphtheria. Other typesof neuritis were seen in smaller numbers. Diphtheria was observed in all itsstages; 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.
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organisms was 17 percent throughout the hospital population.It will be recalled that a similar incidence was reported by Oppel and hisassociates (p. 515) among American troops in the South Pacific.
In the Mediterranean theater, the incidence of diphtheria inthe Fifth U.S. Army was compared with that in the British 10 and 13 Corps and inthe German Heeresgruppe C. The British incidence (expressed as monthlyrates per 1,000 per annum) from September 1943 through the remainder of the yearranged 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 6toward the end of the war. The American incidence was never so high butincreased during the winter of 1944 to 5 per 1,000 per annum and dropped to 1 to2 per 1,000 in early 1945. Italian civilian figures were unavailable, but it isknown that Florence had severe epidemics in 1943 and 1944. In the Germanhospitals at Merano, the number of cases of diphtheria were as high as 34 permonth. 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 physiciansclaimed an incidence of 5 to 10 percent myocarditis and of 90 to 95 percentneuritis and a mortality of about 18 percent. This extraordinary situation wassuspected to be the result of poor antiserums. The Germans estimated polyneuritis asoccurring in 12 percent, myocarditis in 3 percent, anddeath in 1 percent. These figures cannot be considered reliable and certainlyunderestimate the number of cases of diphtheria for, within the variousarmies 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 pharyngealcases followed by the complete typical neuritis with palatal accommodation andlimb palsy. A second group of 14 patients had pharyngitis and typical neuritiswithout cultural evidence of diphtheria. A third group of two cases wassimilar except that a history of palatal and accommodation palsy could not beobtained, although the paralysis of extremities was identical with that found inthe others. These two were classed as probable diphtheria. All three groups (42cases) were combined and analyzed. The other types of neuritis (to be discussed)were clinically different, and in all but nine the distinction was greatenough for a clear separation from diphtheritic neuritis. In these cases,along with a control group without sole throat or neuritis and with a grouprecovering from pharyngeal diphtheria without neuritis, cultures were madeon 2 days, and the amounts of antitoxin in the serums were determined (table98). Of the controls, approximately 17 percent had positive cultures, a figure exceeding the incidence in diphtheritic neuritis, which wasapproximately 12 percent. The patients with nondiphtheritic neuritis werepositive in about the same percentage (18 percent) as the controls. Nopositive cultures were noted in the 13 cases due to sulfonamides. Theamounts of circulating antitoxin did not differ significantlybetween the
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groups, whether with positive or negative culture, but were higher inpatients convalescent from diphtheria than in those with diphtheriticneuritis.
Clinical classification | Number of cases studied | Number of cases cultured | Culture positive for virulent | Antitoxin content of serum | Culture negative for virulent | |||||||
|
| <0.01 unit | >0.01 unit | <0.01 unit | >0.01 unit | |||||||
| 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 |
|
|
| 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 establishinga retrospective diagnosis of diphtheria. Nevertheless, the neuritis ofdiphtheria is so characteristic that the author believes it can be diagnosed onclinical grounds with considerable assurance. By 1944, it had thus becomeevident that diphtheria was a major cause of neuritis in all theaters ofoperations. In the regions where factors conducive to ulceration of the skinprevailed, 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 toproduce difficulty with speech, swallowing, and sight, followed by a slow, tin-
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gling symmetrical palsy of the limbs. The paralysis developsand clears sequentially in one place after another in a leisurely pattern overmany weeks, ending finally in complete recovery. The few fatalities result frommyocardial failure, respiratory paralysis, or pneumonic complications of thelatter. Paralysis of accommodation is a specific feature and results fromweakness of the ciliary muscle. Pupillary reactions are unaffected.
Gaskill and Korb,23 who had the exceptional opportunity tofollow many patients throughout their illness, described the development ofneurological changes in cutaneous diphtheria thus:
The clinical course of the neuritis proceeded in regularsequence through certain definite steps, which were in some cases partiallysuperimposed, and in others quite separate. The steps in order of theirappearance were (a) cranial nerve, (b) peripheral nerve (sensory), and (c)peripheral nerve (motor) involvement.
Gaskill and Korb noted that the cranial nerve palsies lastedfrom 10 to 30 days and that as these were clearing up, or after an interval of aweek or 10 days, the patient would then notice numbness and tingling of thehands 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 aftera latent period of 1 to 4 weeks. The motor phase lasted from 6 to 12 weeks. Theaverage case lasted about 100 days.
Onset and Duration of Neuropathic Involvement
The evolution of neurological involvement and the structuresaffected in cutaneous and pharyngeal infections were somewhat different. Walshe,24in World War I, described a local paralysis related to the site of the ulcers;he considered palatal paralysis an example of local paralysis in pharyngealinfections. Gaskill and others, however, in their cases did not observe thislocal paralysis in cutaneous diphtheria and noted a longer interval before theonset of the neuritis than in pharyngeal diphtheria. Liebow and his associates(p. 515) observed neuritis from 2 to 7 months after the appearance of cutaneouslesions. It is quite possible that the ulcers might have become infected with C.diphtheriae secondarily at any time in their course, but these workersdescribed two patients from whom virulent C. diphtheriae were culturedfrom cutaneous lesions 2 and 4 months before the onset of the neuritis. InGaskill's patients, the onset of neuritis was quicker and averaged 70 daysafter the ulcers developed, with a range of 23 to 158 days.
In patients with pharyngeal diphtheria, the interval wassomewhat shorter although there was much variation. Thus, Perkins and Laufer (p.515), in 16 patients with faucial diphtheria and in 5 patients with cutaneousulcers, noted that in the former the interval to onset of palatal or other
23Gaskill, H. S., and Korb, M.: Occurrence of Multiple Neuritisin 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.
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cranial nerve palsy averaged 26 days, with a range of 14 to41 days; the cranial nerve palsies lasted on an average of 15 days, with a rangeof 4 to 35 days. The sensory neuritis developed in an average of 5 weeks aftersore throat, with a range of 3 to 11 weeks; it reached a maximum in 25 days,with a range of 1? to 6? weeks; and the time from the peak to recoveryaveraged 8? weeks. Motor symptoms appeared at the same time as sensorychange or a little later. In their patients with cutaneous diphtheria, the interval to onset averaged3? months, with a range of 2?to 5 months.
Similar data were reported by Sampson (p. 515) in 20patients, 10 of whom had cutaneous ulcers with the onset of neuritis from 4to 9 weeks after the ulcers developed. Copsey (p. 515), in 17 patients, largelywith pharyngeal diphtheria, found that the onset of neuritis was from 3 to 8weeks after the appearance of sore throat. In Gammon and Schoenbach's 42diphtheritic cases (p. 519), 5 of which were cutaneous, the palatal paralysisbegan from the 1st to the 12th week, most frequently in the 2d to 4th week (chart5). Paralysis of accommodation appeared a little later, from the 2d to the8th week, most frequently in the 3d to the 6th. The limbs were involved mostoften in the 5th and 6th weeks, with a range of 2 to 13 weeks (chart 6). (Seealso table 99 and chart 7.) The neuritis of the extremities reached a maximum in1 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, ofaccommodation, and of the extremities, in weeks, after pharyngitis
begun to improve by 6 weeks; half by 8; and three-quartersby 12 weeks. At the time of examination, only one patient had fully recovered.
These various reports emphasized the characteristic slowevolution of the process over many months and pointed out that its duration wasa measure of the severity of the disease. Regardless of the time involved, thesequential steps were maintained, although the process might reverse itself atany stage and the full picture might never develop. On the other hand, in themost seriously sick, the paralysis progressed to involve the trunk, head, andneck, leaving the patients completely helpless. In these patients, disabilitywas of the longest duration.
Structures Involved
The incidence of palatal paralysis in pharyngeal diphtheriawas from 7 to 10 times greater than that in the cutaneous form, while theincidence 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 eachtype of disease, whereas palatal palsy was seen in only 10 percent of patientswith cutaneous diphtheria but in 70 to 100 percent of those with pharyngealinfection. It should be noted, however, that the incidence of ciliary paralysismay actually be higher than reported for it is easily overlooked by the patient.
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TABLE 100.-Distribution of the neurological involvement in diphtheritic polyneuritis (in percentage)
Area of involvement |
| |||||||
| 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
| 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 | --- | --- |
|
| 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.: DiphtheriticParalysis Clinical and Anatomical Data. J. Med. Lyon 28: 481-496, 1947. (5)Brown, M. R.: The Mechanism Involved in Polyneuritis as Exemplified byPost-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 ofPost-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 CutaneousDiphtheria. Arch. Neurol. & Psychiat. 55: 559-572, 1946.
Source: Gammon, G. D.: Effects of Bacterial Toxins on theNervous 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 hadpreviously suffered from a palatal palsy that had disappeared.
The muscles innervated by other cranial nerves may also beaffected in diphtheria. Esophageal paralysis occurred in 10 to 30 percent;pharyngeal paralysis, in 5 percent; and laryngeal paralysis, in 10 to 20percent. Squint occurred in 10 to 20 percent; any of the ocular muscles may beaffected. Sensory symptoms of the tongue and face, usually paresthesias, mayaffect some 10 percent, as may palatal anesthesia. Loss of taste has been notedby Gaskill and Korb (p. 521), but facial hypalgesia rarely occurred. Facialparalysis is of special interest. Since it is a feature of the Guillain-Barr?
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syndrome, its presence in diphtheritic neuritis sometimes ledto confusion in diagnosis. Usually unilateral, it reached an incidence of 20percent in some series, varying from 0 to 10; Walshe (p. 521) found it in 7percent of patients with cutaneous diphtheria. Johnson (pp. 516 and 517)reported it in 14 percent of patients, occurring unilaterally in half andbilaterally in half.
In Gaskill and Korb's patients with cutaneous diphtheria,35 percent developed palsies of cranial nerves and all had involvement ofperipheral nerves. Slightly fewer began with palsies of cranial nerves; somebegan with both simultaneously. The onset in the cranial nerves forecast a moresevere neuritis in the patients with cutaneous diphtheria in contrast to thepatients with pharyngeal involvement, many of whom had signs referable tocranial nerves but never developed the symptoms affecting the limbs. It is aquestion whether all cases that had involvement of cranial nerves only cameunder Gaskill's observation. No cases of hemiplegia due to embolism from theheart 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 ofthe illness, long before the ensuing neuropathic sequence, developedparesthesias in the limbs, suggesting a segmental or root arrangement. Thisin some involved the ulnar border of the forearms or hands; in others, there wastingling about the face and tongue. Commonly, however, symmetrical tinglingparesthesias were felt in the distal parts, beginning in the fingers and hands,or toes and feet, or most often in both regions simultaneously and symmetricallyon the two sides. Patients described this as "the tingles," a sense ofthe limb being "asleep" or numb. They seldom (in less than 10 percentof cases) spoke of pain. If present, it was described as a "pins andneedles" sensation, never very severe nor necessitating analgesics. Veryrarely, this mild pain replaced the tingles and rarely did paresthesias precedethe weakness. At this stage of paresthesia, hyperrefiexia, often mentioned butseldom seen, occurred, as well as tenderness of muscles, especially the smallmuscles of the hand. Walshe (p. 521) reported that this muscular tendernessanticipated all other signs of neuritis; the author was also impressed by thisfinding although most of the reports quoted previously minimized it.
The paresthesias ascended in 1 to 2 weeks to the forearms andlegs; only occasionally did they reach the root of the limbs. At this time,examination disclosed sensory impairment, its character differing from patientto patient and from one group to another. Loss of vibratory or positional sensehas been emphasized in the past. Perkins and Laufer (p. 515) in their
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excellent report, which stressed the importance of thesensory findings, noted that the vibratory and the stereognostic senses weremarkedly affected; the tactile sense, moderately; and the perception of pain andtemperature, only slightly. In contrast, all of Gaskill and Korb's seriesshowed hypesthesia to pain, temperature, and light touch; only 8 patients out of140 had a loss of vibration and sense of position, and in these alone was ataxianoted. In Gammon and Schoenbach's study (p. 518), in a series of 37 cases ofnasopharyngeal diphtheria, 20 showed objective sensory involvement. Impairmentof the perception of pain and of the tactile, but not of the vibratory orpositional, sense was the most frequent combination (10 cases, 4 of whichshowed ataxia). No patient was observed with impaired vibratory and positionalsense and normal tactile and pain sense. Ataxia was found eight times in 13patients without objective impairment of sensory response to pinprick, touch,vibration, or position; 10 of these patients complained of tingling and 1 ofpain.
Thus, a dissociation of sensory impairment has often beenencountered, and ataxia has been observed without objective sensory loss. Thelack of emphasis previously put on the sensory changes probably is due to thefact that diminution is much more frequent than complete loss. Alsochildren, who predominate among patients reported in the literature, describethese symptoms less clearly. In distribution, these sensory changes are mostoften of the glove-stocking type, but many cases have shown a root or segmentalor cord type. For example, Gaskill and Korb reported a loss of vibratorysense at the thoracic level; others noted a similar loss over the trunk. Thesedata demonstrated that the process was not confined to nerve or root butinvolved the cord as well. In diphtheritic ulcers, the scar and a zone of 1 to 2mm. around it are anesthetic. The paresthesia may cease in 1 to 4weeks before weakness develops, or, more frequently, the two may overlap.
Motor signs developed with fatigability progressing to aflaccid palsy, more marked peripherally. The paralysis was usually symmetricalin onset and extent with minor differences in either. Atrophy developed ifparalysis was severe. The lower limbs bore the brunt, and thigh as well as calfand foot were involved. The lower limbs were weak in twice as many cases as theupper limbs. The paralysis was much more marked than the sensory loss and attimes it was complete in the extremities. In a smaller number of cases (10percent), it involved the trunk and neck, leading to complete immobility. Insuch cases, loss of control of the sphincters ani sometimes occurred. In a smallnumber of cases, there was intercostal and diaphragmatic paralysis. The degreeof palsy varied enormously. Gaskill and Korb found the quadriceps and interosseiespecially susceptible. Loss of reflexes followed the distribution of theweakness. The ankle and knee jerks were most often affected; the biceps andtriceps, less often. Loss of the abdominal reflexes was noted by Perkins andLaufer. The loss of reflexes may be permanent. Recovery in sensation precededrecovery from the weakness and both were usually
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complete; however, Copsey commented on the painfulness of thefeet in reambulation, and Liebow and his associates described one patient withpermanent atrophy of the deltoid with a winged scapula.
Antitoxin in Relation to Diphtheritic Neuritis and SerumNeuritis
The experience of World War II confirmed the observationsfound in the older literature that antitoxin given early-within the first 3days of infection-prevents or greatly diminishes the changes of neuropathy,but is valueless after its onset. In fact, it may induce a primary serumneuritis, which may be local in the limb of injection, or may be widespread. Ineither case, pain and hyperpathia are prominent symptoms and are often severe.This manifestation may occur in addition to a diphtheritic neuropathy. Cases ofthis kind are quite unlike the usual diphtheritic neuritis, as illustrated bythe following:
A man, 44 years old, with proven nasopharyngeal dipththeriawas 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 feetoccurred, accompanied by severe pain and weakness in both hands and forearms.All these symptoms regressed during the next 2 weeks with complete restorationto normal at the end of this period. During the height of the process, decreasein cutaneous sensation along the ulnar border of the hands was noted; the tendonreflexes were normal.
A 36-year-old male, with unproven but clinically typicalpharyngeal diphtheria, was given 18,000 units of antitoxin on the second day ofdisease. Typical diphtheritic neuropathy ensued, with palatal palsy in the thirdweek, 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 afterthe 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 allthe limbs rapidly became weaker. Decreased awareness of temperature and pain andloss of tactile and vibratory senses were noted in the legs, and the patient hadlittle use of his upper or lower extremities.
Spinal Fluid
All the observers quoted previously noted increased amountsof protein in the spinal fluid without increase of cells in diphtheriticparalysis. This fact had not been previously emphasized in the Americanliterature and unawareness of it led to confusion with the Guillain-Barr?syndrome. Guillain had originally stated that the amounts of protein in thespinal 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 diagnosisof infectious polyneuritis (p. 531), for, in fact, many cases never have suchlarge amounts. Older accounts reported an early slight increase in cells, butthis 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 theprotein 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 200mg. percent or lower were more usual. The results of tests with colloidalmaterials were sometimes abnormal, and a midzonal curve was characteristic. Insome cases, it was many weeks before the protein returned to normal; Gaskill andKorb found that, when the patients were clinically well, the spinal fluidprotein had returned to normal.
Pathogenesis and Pathological Anatomy
In the author's review of the effects of bacterial toxinson the nervous system,25 the recent literature was summarized,including German reports on their experience during World War II. In allspecies, diphtheria toxin is a general cellular poison affecting most tissues.It seems probable that the initial lesion is biochemical and, as with tetanustoxin, is undetectable by techniques now available. The changes seen are theresults of parenchymal and vascular degeneration, the complications thereof, andthe secondary processes of repair. Peripheral nerves show edema of endoneuraland perineural tissue and the cells of origin show a chromatolytic change. Themyelin sheath and zone degenerate. Nuclei in the spinal cord and brain stem areaffected as well. Muscle is damaged secondarily or primarily. Minute cerebralvascular lesions due to endarteritis or embolic lesions from the heart have beendescribed. Death results from cardiac or respiratory failure, from membranousbronchial obstruction, atelectasis, or from toxemia.26
25Gammon, G. D.: Effects of Bacterial Toxins on NervousSystem. 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 ledhim to suggest that the toxin is the protein moiety of the cytochrome B enzymeof C. diphtheriae and that its effect may result frominterference with the synthesis or activity of this or related enzymes of thehost. Direct proof, however, is lacking, as he found no action of the toxin invitro or in vivo on preparations of cytochrome B. Indirect support, however, isgiven in the observation that, in the silkworm pupa, segmental muscle,containing the enzyme, is poisoned by the toxin, whereas cardiac muscle, lackingit, escapes. Ludwig has recently provided the first evidence of action of thetoxin in vitro on the succinic dehydrogenase system; however, he attributed theeffect to porphyrin present in the crude toxin. (Ludwig, G. D.: The Inhibitionof the Succinic Oxidase System by Coproporphyrin. Proceedings of Physiological Society, Philadelphia, 17 Nov. 1953. Am. J.M. Sc. 227: 358-359, 1954.) Itshould be noted that cytochrome enzymes are all but universally distributed, andtherefore interference with their action would be general, as is the case withthis toxin. In poisoned skeletal muscle, phosphocreatine falls and inorganicphosphorus rises while adenosine triphosphate remains constant.
Wildf?hr has reported that the toxin can be found in theblood of patients a week or two before the onset of neuritis and in the spinalfluid of paralyzed patients. (Wildf?hr, G.: Uber Diphtherietoxingehalt imPatientenblut und Liquor bei Diphtherie-Spathlahmungen. Zentralbl. f. Bakt. (Abt.1) 154: 18-26, 15 May 1949.) Presumably, therefore, all tissues are exposedand the susceptible ones poisoned. As yet, however, the manner of action of thetoxin at a metabolic level is not clear. Rose, in commenting on Gammon'sreview (see footnote 25, above), pointed out that there is no actual proof thatthe toxin has a direct effect on the nervous system and the fact that theneuritis occurs so late raises the question whether one mode of action may notbe the consequence of some type of antigen-antibody reaction. If this be so, anintrinsic antibody must be responsible, for many of these had no detectableantitoxin, and no increase in antibody was detected in serum or by Schick testin patients with diphtheritic neuritis. Furthermore, it is recognized thatantitoxin can initiate a reaction, of one type at least, that is clearlydifferent clinically from diphtheritic neuritis (p. 535).
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There can be no doubt that diphtheria toxin has its ownuniquely selective action on ciliary and on sensory and motor nerves quiteunlike the equally unique effects of botulinus or tetanus toxins. It seemslikely that investigation of its characteristic modes of action at metaboliclevels will yield information concerning the makeup of the tissues that arespecifically 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 virulentmicro-organisms from the infected tissue, the subsequent neuritis, which has acharacteristic clinical course, can with certainty be attributed to the originalinfection. The chances of recovering the micro-organism depend in part onwhether it is suspected and sought in lesions, many of which do not at allresemble membranous sore throat nor fit other textbook descriptions.Furthermore, if the micro-organism is not sought early, it may have disappearedby the time of the onset of neuritis. By then, the frequency of recovery oforganism approaches the rate in the general population of the carriers who arespreading the infections. Thus, 3 weeks after faucial diphtheria, the rate ofrecovery of organisms approximates 30 percent, and it falls off rapidlythereafter.
If recovery of the micro-organism fails, the next question iswhether the amounts of circulating antitoxin found are of sufficient magnitudeto prove infection. The Schick test is of no help, as many of the reports thathave been quoted showed; at the time of the neuritis, patients with positive andnegative Schick reactions were of about equal frequency. Determinations of twolevels of antibody by Bronson (p. 514) failed to demonstrate any differencebetween the patients and their controls. Gammon and Schoenbach's data (p. 519)showed that patients convalescent from faucial diphtheria with neuritis hadantibody levels lower than in those convalescent from diphtheria withoutneuritis or in controls. Furthermore, a lower carrier rate (12 percent) wasfound in the first group than in the control population (17 percent in patientswith neither sore throat nor neuritis; 18 percent in patients withnondiphtheritic neuritis). Mueller (quoted by McGuinness, p. 513) has pointedout that the clinician must decide if the presence of the micro-organismindicates the disease or the carrier state. Thus, neither the amounts ofantibody found nor the results of nasopharyngeal cultures could be used to provethe presence of past diphtheritic infection nor present diphtheritic neuritis.It is obvious therefore that the diagnosis must be made early. The onlyalternative as far as can be seen is discovering the toxin itself in blood orspinal fluid, as has been reported by Wildf?hr27 but, so far as the author isaware, has not been confirmed.
27See footnote 26, p. 529.
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Actual proof of the diphtheritic origin of the neuritis istherefore often difficult and may be impossible. Nevertheless, the diagnosis canbe made with some confidence on the basis of the clinical evolution. For thereasons given, the author does not agree with statements that, lacking thetypical cranial nerve palsies, diphtheritic neuritis cannot be distinguishedfrom infectious polyneuritis of the Guillain-Barr? type.
INFECTIOUS POLYNEURITIS:
THE GUILLAIN-BARR? SYNDROME
Confusion in diagnosis, as has been noted, arose principallyover the distinction between diphtheritic neuropathy and the Guillain-Barr?syndrome through the unwarranted emphasis on the albuminocytologic dissociationin the spinal fluid in the latter, and the difficulty of proving diphtheriticinfection. There has, in fact, been some argument about the extent of theclinical range of the Guillain-Barr? syndrome and whether it represents adisease, as Guillain contended, or a group of conditions. Americans havefrequently considered the albuminocytologic dissociation as diagnostic of"the syndrome," but the English school of neurologists have consideredincrease of the protein in the spinal fluid indicative rather of the severitythan 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; withbrain tumor, especially posterior fossa tumors; in arachnoiditis; in meningealcarcinomatosis; in syphilis; in lead encephalopathy; possibly in sandfly fever;and in other conditions.
There is no doubt, however, that there does exist a group ofcases fitting Guillain's criteria and showing a combination of facial diplegia,peripheral neuropathy, and increased amounts of protein without cellularincrease in the spinal fluid. Typically, the onset in such cases is abrupt, andaccompanied by pain, and the peak is reached within a short time-usually aweek or 10 days; the prognosis for recovery is favorable if the acute phase issuccessfully passed. These patients often have a preceding pharyngeal,respiratory, or gastrointestinal illness which seldom causes much complaint, andthe neurological symptoms appear, as in diphtheria, with little or no evidenceof 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 facialmay be involved, with or without peripheral neuritis. The motor findingsfrequently overshadow the sensory, and the weakness may be more proximal thandistal. Paralysis of accommodation or pharyngeal paralysis is seldom reported.The cause of the polyneuritis is unknown, and the diagnosis rests on theclinical picture and examination of the spinal fluid.
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Diagnostic uncertainties plagued medical officers in theMediterranean theater where typical examples of the Guillain-Barr? syndromewere unquestionably seen among the more numerous cases of diphtheritic neuritis.Johnson's final analysis of 155 cases (p. 517), however, showed that, althoughthere were 73 diagnoses (approximately 42 percent) of the Guillain-Barr? syndrome,this syndrome existed in only 10 patients (6 percent). These 10 patients showedthe typical facial diplegia, but there were others that did not, only the limbsbeing affected. In certain patients, the course was that of an acute ascendingparalysis of the Landry type, as in Johnson's Case 90, described asfollows:
In this patient, a transient diarrhea was followed in 3 daysby pains in the lower back and buttocks and down the back of the thighs andlegs; 2 days later, severe weakness suddenly developed in the lower extremitiesand then in the hands. All deep tendon reflexes were absent. Sensation wasintact, except for a slight decrease in vibratory sense, and cranial nervefunction was normal. In the next 2 days, the trunk muscles were involved and thepatient died with pneumonia 2 weeks after the onset of the diarrhea. Autopsyshowed pulmonary atelectasis with bronchopneumonia. The spinal roots showed aprimary inflammatory reaction with secondary degeneration of the anterior horncells and patchy demyelinization of the roots. The spinal fluid proteinmeasured 113 mg. percent.
A study of the cases reported in the war reveals that arather small number were due to infectious polyneuritis of the type described byGuillain, Barr?, and Strohl. The author agrees with Guillain that the clinicalpicture and course of disease distinguishes these cases from diphtheriticneuritis even if the latter shows bilateral facial involvement. It is importantto make this distinction in order that such cases may be studied for causativeagents. To combine all patients with peripheral neuritis on the basis ofelevated protein without cellular increase in the spinal fluid would hindersuch inquiry. We have already seen how it delayed the recognition of cases ofdiphtheritic 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 withrecurrent attacks of malarial fever as follows: "The typical clinicalpicture was one in which 'irritative' phenomena were present, with sharp orstinging pain in the distribution of a peripheral nerve, followed by an * * *actual muscle contraction, intense hyperalgesia, and increasedsweating." In the milder cases, numbness and tingling occurred. Thesymptoms were always increased with recurrence of the malaria. The nerves orroots were involved symmetrically, alone or in combinations in the lowerthoracic, the trigeminal, or the sciatic regions. The axillary nerves as well asothers
28Delp, M. H., Sutherland, G. F., and Hashinger, E. H.:Post-Diphtheritic Polyneuritis; Report of 5 Cases With AlbuminocytologicDissociation Simulating Guillain-Barr? Syndrome. Ann. Int. Med. 24: 618-628, April 1946.
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of the upper extremities were also at times affected. Duringthe acute attacks, the muscles of the limbs were usually flexed at the forearmsand wrists, and attempts to straighten them greatly increased the pain. Thehyperalgesia lasted several weeks. Occasionally, hypalgesia and hypesthesia werenoted. It was suggested that the symptoms might be attributed to vascularlesions of the nerves. Plasmodium vivax was the common type ofthe associated infection, although mixed infections were suspected in somecases. Some 18 of 100 relapsing cases of malaria showed a milder form of thedisability.
After other severe infections-Neuropathy has also beendescribed with severe sepsis, whatever the cause, as well as with diphtheriaand other specific infections, such as the cases attributed to malaria byHarvey, and those ascribed by Wilke to dysentery in German patients followingShiga infections (noted by Johnson). These last had an albuminocytologicdissociation in the spinal fluid.
Neuropathy following pneumonia is illustrated by thecourse of disease in a 37-year-old man who had tropical ulcers of the legs, fromAugust to October. On 23 March, bilateral bronchopneumonia developed, whichwas treated with a sulfonamide eubasin. About a month later, after the patienthad improved but was still febrile, he awoke to discover weakness in thelegs, hands, and fingers. There were no pains or paresthesias. The weaknessincreased for 3 weeks and he could barely walk. The small muscles of the handsand legs were wasted and the quadriceps were weak. The patient was ataxic andhad 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, butthe biceps and triceps were normal.
In four other cases, septic wounds led to delirium and othersigns of toxic psychosis and to a neuritis identical in course with thepostdiphtheritic cases except for the lack of palatal or other cranial nerveinvolvement, symptoms of which, however, might have been undetected. Only one ofthe whole group of six patients had a slightly elevated cerebrospinal fluidprotein (67 mg. percent). Diphtheria could not be ruled out in these cases, butsimilar ones have been noted in civil life where diphtheria was not a factor.
In a patient reported by Zimmerman and Lowry,29infectioushepatitis was followed by a typical motor and sensory polyneuropathy of theGuillain-Barr? type, with unilateral involvement of facial nerve. The conditionprogressed for 17 days and then improved to the point of complete recovery in 4months. The protein in the spinal fluid measured 192 mg. percent.
29Zimmerman, H. J., and Lowry, C. P.: Encephalomyeloradiculitis (Guillain-Barr? Syndrome) as a Complication ofInfectious 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 ofperipheral neuropathy, mostly peroneal and axillary, cause unknown. These caseswere said to resemble the group described by Spillane30 and were clearlydistinguishable from the cases associated with recurrent malaria (p. 532). Theauthors described the conditions as characterized by the sudden onset of motorand sensory involvement, usually of a single nerve. Function, in most cases,returned within 4 to 6 months. In 15 cases, the common peroneal nerve wasattacked; in 3, the axillary nerve; and in 1, the radial. Typically, the patientawakened to find weakness; this reached a peak within 1 to 3 days. About aquarter of the patients complained of pain, which was especially sharp andburning in the axillary type. This feature was emphasized by Spillane in a studyof 46 patients, most of whom had served in the British MEF (Middle East Forces).Some patients had "pins and needles" paresthesias lasting from a fewdays to a few weeks. Sensory loss over the dorsum of the foot or lateral surfaceof the leg was noted in over half of the patients with peroneal involvement; theaffected area was surrounded by a zone of intense hyperesthesia. In the patientswith axillary involvement, sometimes other branches of the brachial plexus wereaffected. Spillane described pain in the chest wall. Electromyography was usedto trace the degree of involvement and recovery. Two of the patients withaxillary neuritis showed atrophy with no recovery in 6 months. The author hasseen similar patients without recovery in over a year, and similar casesoccurred among those described by Johnson in the Mediterranean theater. One ofthe patients with peroneal involvement relapsed without known cause after 3months 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 personsin a German prisoner-of-war camp at Alva, Okla., which bore some clinicalresemblance to the disease described by Harvey; that is, one or both peronealnerves and occasionally tibial nerves were affected by tingling parethesias andfoot drop suddenly ensued. Occasionally, the fingers tingled. A blunting ofsensation and decrease in ankle jerks and tone were noted. Improvement occurredin most instances. It is difficult to decide if these cases form a unity, and itis possible that the shoulder-girdle group differs from the peroneal type.Weinstein's suggestion that vaccination was the cause has not been widelyaccepted.
POSTVACCINATION NEURITIS
Postvaccination neuritis was observed by Sabin34inrare cases after immunization against Japanese B encephalitis. It was usually asegmental motor and sensory paralysis in the injected limb, or a complication ofserum sickness. Note has been made of an allergic reaction to diphtheriaantitoxin presenting as a local or general manifestation (p. 528).
The cases reported by Weinstein and Gersten werepredominantly of the shoulder-girdle type. Thirteen cases seen in North Africafrom July 1943 to January 1944 were reported. Later, Weinstein added six morecases and suggested that the cause was due to prior injections. He described thesyndrome as "characterized by a rapid, often painless onset of motorinvolvement with frequently enduring paralysis and atrophy of the affectedmuscles, and a tendency for limitation to a single extremity with a predilectionfor the shoulder girdle." In most instances, there was multiple but localnerve involvement, which in some cases was asymmetrically bilateral. The onsetwas always rapid and at times sudden, the victim awakening to find paralysis ofarm or shoulder. A sensation of numbness or deadness was frequent, but actualpain was present in only 7 of the 19 cases and was severe and persistent in only2, each with involvement of the axillary nerve. In 16 cases, an upper extremity was affected, and in 4patients both arms were involved asymmetrically. The brunt of the paralysis fellupon the shoulder girdle, usually with multiple neurological involvement. Thefollowing nerves were affected: Axillary, 6; long thoracic, 6; thoracodorsal,dorsoscapular, suprascapular, and radial, each 4; and musculocutaneous ulnarand spinal accessory, each 2. Isolated unilateral common peroneal palsy wasnoted twice. Sensory impairment was less conspicuous than palsy and was foundchiefly 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, ClinicalManifestations, 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. Palsywas maximal at onset and not progressive. Recovery was noted in about half thecases within 2 to 3 weeks, but the others remained paralyzed and atrophy ensuedwithout fasciculations. The spinal fluids were normal.
Considering various possible causes, Weinstein commented onthe absence of prior or current infection, although the late stage resembledpoliomyelitis. No toxic agents, including sulfonamides, were implicated, andthere was no suggestion that pressure had been operative. The only common factorwas prior injection of vaccine, toxoid, or serum, which had been given to eachof this group within 2 weeks to 3 months. None had serum sickness. For thisreason and because the type of involvement resembled that of postvaccinationneuropathy, Weinstein attributed the cases to this cause. He placed theincidence second to postdiphtheritic neuropathy. There is no doubt thatpostvaccination neuropathy occurs without serum sickness. The interval is longerafter injection in Weinstein's cases than that usually recognized. Spillane(p. 534) did not associate his similar cases with this cause. Localization ofpoliomyelitis to an injected area has been noted. In most descriptions ofpostvaccination neuropathy, pain is however a prominent feature. It would thusappear that Weinstein's suggestion, while a valuable one, requiresverification.
NEURITIDES CAUSED BY TOXIC AGENTS
After sulfamethylthiazole in gonorrhea-Sulfamethylthiazole,which had been rejected in the United States when it was found toproduce "anterior horn cell disease," was purchased surreptitiously inItalian pharmacies by German soldiers for the self-treatment of gonorrhea. Itproved highly active for it "cured the gleet and dropped the feet."
Gammon and Schoenbach studied 13 patients in whom the onsetwas abrupt, with more or less severe pain in the legs and feet, followed in 1 to7 days by the sudden onset of weakness. The maximum involvement was reached atthe earliest in a week and in the other cases a few days later. All patientswere 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 highlyselective. The muscles of the thenar eminence, especially the short flexor ofthe thumb, were affected, and occasionally the weakness spread to the first andsecond interosseous muscles. The paralysis was flaccid and followed by atrophyand cessation of pain. The ankle jerks were lost, but the knee jerks and thetriceps and biceps reflexes were unaffected. Sphincters were also unaffected.Only 2 of the 13 patients showed a slightly impaired sensory response topinprick and light touch below the knees. The process was essentially aselective symmetrical paralysis with painful onset. Improvement was slow andincomplete with atrophy a permanent residuum in some cases, and only half thepatients had shown any
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improvement when examined. This began in the first to fifthmonths after onset. Two patients had a relapse, one after a second course ofsulfonamide and the other after treatment with olobintin, a derivative ofturpentine. 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 afterstopping the medicine. They also stated they had encountered the condition onlyduring the treatment of gonorrhea and no other diseases. The condition resembledthe neuropathy after Uleron, a disulfanilamide, and the triorthocresol "jake"paralysis. The symmetrical involvement distinguished these cases from the groupstudied by Harvey and his coworkers and by Spillane.
Trinitrotoluene toxicity.-Neuritis in munitionmanufacturers was reported in World War I. At the request of Dr. L. C.McGee, medical director of the Hercules Powder Company, the author, with Armyordnance and U.S. Public Health Service officials, saw eight patients suspectedof this condition in a plant at Chattanooga, Tenn. Some of them showed anobviously hysterical sensory loss in the limbs and a few had tinglingparesthesias of the limbs lasting several months. Sensory tests suggested animpairment of pain and temperature sense in a glove-stocking distribution,occasionally sparing the palms and soles. The motor weakness of which somecomplained was largely subjective. Tendon reflexes were unaltered. Cranialnerves were unaffected. The spinal fluid was not examined. The subjective natureof most of the complaints quite naturally led to conflicting interpretations ofthe 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 controlmethods 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 wereencountered-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 summarizedby Denny-Brown.37 These neurological manifestations arose chiefly inprisoners, particularly in the Eastern theaters of war. Malnutrition as a causeof neuritis outside the prisons was unusual unless accompanied by otherdiseases, such as dysentery, and accordingly did not often present a diagnosticproblem.
SPECIAL PROBLEMS IN DIFFERENTIAL DIAGNOSIS
Hysteria-Hysteria, as well as other diseases of thenervous system, had to be distinguished in patients with neuropathy, just as thevarious types of neuropathy had to be distinguished from each other. Hystericalparalysis was frequently suspected until clear evidence of organic disease wasuncovered. Findings indicative of toxic myocarditis and the discovery ofelevated amounts of protein in the spinal fluid frequently clarified thediagnosis as did also the gradually growing acquaintance with the varioussyndromes.
Poliomyelitis.-Frequently, poliomyelitis had to beconsidered because, as a result of the transfers through various installationsout of combat areas, adequate study was made late, at a time when the cells inthe spinal fluid had diminished and the protein was still elevated. It is knownthat this rises several weeks after infection and may remain elevated formonths. The pharyngitis or gastroenteritis of poliomyelitis is followed in a fewdays by paralysis, which reaches its peak in a few days at most. The onset maybe painful, but sensory loss is not found with the exception of the rare case oftransverse myelitis presenting a sensory level. The older clinical suspicionthat poliomyelitis could cause such a condition has now been confirmed by meansof the newer diagnostic tests. The Landry type of poliomyelitis ending fatallycould not be distinguished from that of other causes unless there was sensoryimpairment. Bulbar poliomyelitis also proved difficult to distinguish from theGuillain-Barr? syndrome. As a rule, however, the asymmetrical and patchydistribution of paralysis and atrophy permitted the differentiation fromneuropathy.
Infectious mononucleosis.-This occasionally involves thenervous system and one form resembles the Guillain-Barr? syndrome. Ricker,Blumberg, Peters, and Widerman38 reported two fatal cases, with postmortem study at the Army Institute of Pathology (now the Armed Forces Instituteof 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, andDepartment of Defense Pursuant to Public Law 744, 83d Congress, 2d Session, subject: Effects of Malnutritionand Other Hardships on the Mortality and Morbidity of Former U.S. Prisoners of War and CivilianInternees of World War II: An Appraisal of Current Information.
37Denny-Brown, D.: Neurological Conditions Resulting From Prolonged and Severe Dietary Restriction (Case Reports inPrisoner-of-War,and General Review). Medicine 26: 41-113, February 1947.
38Ricker, W., Blumberg, A., Peters, C. H., and Widerman,A.: Association of Guillain-Barr? Syndrome With Infectious Mononucleosis, WithReport 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. Deathoccurred from respiratory failure and atelectasis with pneumonia. Specimensof spinal fluid showed a modest pleocytosis and elevation of protein.Pathologically, the process was a widespread acuteneuromeningomyeloencephalitis. Inoculation of specimens of the brain and of thespinal cord from one patient into mice and guinea pigs caused no disease. Theauthors pointed out that certain patients with peripheral paralysis have, unlikethose with poliomyelitis, a good prospect for recovery.
Mumps.-Mumps meningoencephalitis with neuropathy wasreported by Gellis, McGuinness, and Peters39 in an outbreak in Army troops.
Compression.-Compression from tumors or herniated diskswith Froin's syndrome in the spinal fluid gave rise to some confusion untilcollateral evidence of cord disease developed. Unrecognized shell fragments inthe brachial plexus or compression by cervical rib, scalenus anticus muscle, ortraction, or pressure from various sources were rare causes of confusion.
Alcoholic neuropathy-This was not often a diagnosticproblem. Alcoholic neuropathy evolves acutely with a good deal of pain and canbe readily recognized.
Tabes dorsalis-Tabes dorsalis was easily distinguishedby serological and spinal fluid studies as well as by the slow course.
Sandfly fever-This fever entered the diagnosticpicture in Italy, owing to the aches in the limbs and the changes in the spinalfluid that were occasionally found. In such cases, there was usually alymphocytic pleocytosis as well as a rise in the protein. Paralysis was notnoted. A somewhat similar picture was seen in a group of German prisoners withquintana or Volhynia fever (trench fever). This entity has not been encounteredsince World War I. The dramatic fever curve with a rise every 5 days for fiveor six episodes disclosed the diagnosis.
Beriberi neuropathy.-This was a differential problem inonly a comparatively few instances involving prisoners or in association withother disease, particularly in the Far East.
One of the chief difficulties arose when multiple possiblecauses existed in the same person, such as malnutrition, in an area wherediphtheria was endemic. It was not always possible to separate the influenceof each, or the combined effect of all.
CONCLUSION
Two entities could be separated on the basis of theirdistinctive clinical course. One was found in groups of patients withshoulder-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 wasasymmetrical and frequently led to permanent atrophy. The other entity was thecondition described by Harvey with severe pain and cramping phenomena inassociation with relapsing malaria.
The chief diagnostic problem was posed by the Guillain-Barr?syndrome in relation to diphtheritic neuritis. Proof of prior infection withdiphtheria frequently could not be reliably demonstrated by recovery of themicroorganisms, by the Schick test, or by the amounts of serum antibody.Diagnosis was made more difficult by the fact that the pharyngeal infection neednot be present since extrafaucial sites may exist, and the laboratory methodsrequire great skill and experience. The Guillain-Barr? syndrome, on the otherhand, may occur in association with diphtheria, malaria, poliomyelitis, andother infections. Its presence did not constitute a definitive diagnosis initself, nor is it constantly characteristic of any of these conditions, exceptinfectious polyneuritis of unknown cause, and diphtheritic neuritis.
The diagnosis in the end rests on the clinicalconsiderations. In both diphtheritic neuritis and the Guillain-Barr? syndrome,the same region may be attacked. Thus, facial diplegia may occur in diphtheriticneuropathy and pharyngeal paralysis with the Guillain-Barr? syndrome. But theincidence of the facial diplegia is very much higher in the latter condition andpharyngeal paralysis in the former. Ciliary palsy is considered specific fordiphtheria, but it is discovered in only a third of the cases. Furthermore, ithas been claimed that it may be found in the Guillain-Barr? syndrome, thoughthis is open to question.
There are, however, differences between the two whichcharacterize the bulk of the cases. In diphtheritic neuritis, the course slowlyevolves over weeks to reach its peak, while infectious polyneuritis is abruptand quick in reaching its maximum. Pain is more typical of the latter andtingling paresthesias of the former. Based on these criteria, there are twotypical syndromes that can be readily and reliably distinguished. Even lacking ahistory of the early cranial nerve palsies of diphtheria, the later tinglingparesthesias followed by paralysis can be recognized. Although in the majorityof cases the condition can be identified by the differences in the time ofevolution, variations may be encountered in any toxemia, depending on the doseof the causative agent. Thus, Johnson reported a few cases with abrupt onset ofparalysis of the limbs in diphtheria; but this is a great rarity. On the otherhand, there are undoubtedly cases of polyneuritis with facial diplegia with slowsubacute development over weeks; many of these patients have no paresthesias orpain while the paralysis is increasing. Such cases are customarily classifiedwith the Guillain-Barr? syndrome. Again, there are cases with abrupt onset ofmultiple neuritis of the limbs without facial involvement; these may be distinctor a variant of the Guillain-Barr?
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syndrome. Other cases with signs referable to cranial nervesbut without involvement of limbs have also been grouped with it.
These clinical distinctions must accordingly be maintaineduntil the various causative agents can be defined, when a reclassification canbe made that embraces the full range of the clinical picture. If this is notdone, there is danger that a specific causative agent may be mistakenly believedto be operative in producing the group as a whole. Thus, if viral studies weredone in a case of unrecognized diphtheritic neuropathy, the erroneous conclusionmight be reached that a virus was not responsible for any of the conditionsfalling in the wide spectrum of the whole group, while actually unrecognizedviral disease might account for some of them.
In patients with diphtheria, antitoxin is not indicated afterneuropathy has developed for it does no good and may add an allergic neuropathyto the other. Rest in bed in the presence of myocarditis must be enforced toavoid a fatal outcome. In patients with respiratory paralysis orpharyngeal-laryngeal paralysis, due to any cause, prevention of pneumonia is anequally serious problem. In the main, rest until beginning improvement isessential, along with general measures of physiotherapy and adequate diet.Supplementary vitamins apparently do not influence the course of disease.
