J Neurol Neurosurg Psychiatry 1999 Logina 433 8

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Diphtheritic polyneuropathy: a clinical study andcomparison with Guillain-Barr syndrome

Inara Logina, Michael Donaghy

AbstractObjectivesandMethodsClinical features

of 50 adults with diphtheritic polyneuropa-thy (DP) were studied in Riga, Latvia andcompared with 21 patients with Guillain-Barr syndrome (GBS).

ResultsNeurological complications oc-curred in 15% of patients admitted to hos-pital with diphtheria and usually after

severe pharyngeal infection. Bulbar dys-function occurred in 98% of patients withDP and only 10% of patients with GBS.

Limb weakness was mild or absent in 30%of patients with DP. Ventilation dependentrespiratory failure occurred in 20% of

patients with DP. The first symptoms ofDP occurred 250 days after the onset oflocal diphtheria infection. Neurological

deterioration in DP continued for amedian of 49 (range 1583) days andimprovement started 73 (range 20115)

days after onset. In 66% of patients withDP, the neuropathy was biphasic with asecondary worsening after 40 days. By

contrast patients with GBS worsened foronly 10 days on average (range 228 days)and improved after 21 (range 449) days.

Eight patients with DP died, four fromsevere cardiomyopathy and four frommultiple diphtheritic organ failure. Pro-

longed distal motor latencies (DMLs)were common to both DP and GBS, andmore pronounced than motor conduction

slowing. Limb symptoms continued after 1year in 80% of the patients with DP, 6%were unable to walk independently, but

independent respiratory and bulbar func-tion had returned in all survivors. Bycomparison no patients with GBS died

and none were severely disabled after 1year. No death, in patients with DPoccurred after antitoxin on days 1 or 2

after onset of diphtheria symptoms,whereas identical rates of death and peakseverity of DP were seen both in those who

received antitoxin on days 36 and those

who did not receive it at all.ConclusionDiphtheric polyneuropathyis much more likely than GBS to have a

bulbar onset, to lead to respiratory fail-ure, to evolve more slowly, to take a bipha-sic course, and to cause death or long termdisability. Antitoxin seems ineVective ifadministered after the second day ofdiphtheritic symptoms.(J Neurol Neurosurg Psychiatry1999;67:433438)

Keywords: diphtheritic polyneuritis; clinical features;outcome; diphtheritic antitoxin; Guillain-Barr syn-drome

The recent resurgence of diphtheria in centraland eastern Europe1 has provided a modernday opportunity to study the acute demyelinat-ing polyneuropathy which has long beenrecognised as the most common severe compli-cation of diphtheria infection.24 Diphtheriticpolyneuropathy (DP) aVecting the limbs usu-ally follows faucal infection and earlier paraly-sis of the palate. Palatal paralysis and paralysisof accommodation do not tend to follow ante-cedent cutaneous infections, and probablyreflect the regional eVects of locally producedtoxin in faucal infection.5 6 Neuropathy aVectsthe limbs or diaphragm later, up to 3 monthsafter the onset of the diphtheria. Histology

shows segmental demyelination of peripheralnerves, with additional axonal degeneration inthe most severe cases.79

Observations, mainly on children at the turnof the century, showed that DP followed 20%-27% of infections.10 A similar incidence ofneurological complications was found in youngadults during the second world war, with pala-tal paralysis in 15% and polyneuropathy in11%.4 These large studies antedated modernunderstanding of the pathogenesis and electro-physiological diagnosis of acute paralysis,patients were unlikely to survive respiratoryfailure, and antibiotics were not used. Recentdetailed neurological reports on DP in the

English literature have tended to focus on sin-gle cases or small numbers.9 11 12 The benefits ofearly administration of modern diphtheriaantitoxins remain unstudied. However, theannual occurrence of paralysis in diphtheriaincreased from 13.6% to 18.9% after the intro-duction of antitoxin in 1894, in Rollestons(1904) analysis of up to 7000 cases annually.Furthermore, the likelihood of severe paralysisseemed to be reduced only if antitoxin hadbeen administered within the first 2 or 3 days ofinfection.4 10

A fall of immunity in the adult populationhas resulted in a spectacular return of diphthe-ria in eastern European countries, such asLatvia, since 1993, where it had been success-fully controlled previously.13 14 Occasionally,diphtheria had been encountered in Latviafrom 1986 onwards with the epidemic startingin 1994.1517 Adults vaccinated in childhood donot continue to have suYcient immunity toprotect against diphtheria once this infectionreturns to a population. Ten per cent ofrandomly selected Danish men born 195059had lost protection against diphtheria.18 In theUnited States 40% to 50% of persons olderthan 30 years are susceptible to diphtheria19

and 22% of previously vaccinated Danishadults lack protective concentrations of

J Neurol Neurosurg Psychiatry 1999;67:433438 433

Department ofNeurology andNeurosurgery, MedicalAcademy of Latvia, P

Stradins ClinicalHospital, 13 PilsonuSt, Riga, LV-1002,LatviaI Logina

Department of ClinicalNeurology, University

of Oxford, RadcliVeInfirmary, Woodstock

Road, OxfordOX2 6HE, UKM Donaghy

Correspondence to:Dr I Logina, Department ofNeurology andNeurosurgery, MedicalAcademy of Latvia, PStradins Clinical Hospital,13 Pilsonu St, Riga,LV-1002, Latvia.

Received 21 September 1998and in final form29 March 1999Accepted 7 April 1999


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antitoxin.20 As a result of this resurgence ofdiphtheria, mass reimmunisation of adults wasundertaken in Latvia during 1997. Thus DP isa particular diagnostic possibility in middleaged patients with acute polyneuropathy de-spite diphtheria vaccination in their childhood.We studied the clinical evolution of polyneu-ropathy, and the influence of antitoxin, duringthis recent outbreak of diphtheria in Latvia.Patients with DP were compared with patients

with GBS encountered in the same hospital;GBS has a relatively stable incidence of 1 to2/100 000 population.21 22

MethodsPATIENT POPULATION

Fifty patients with DP and 21 patients withGBS were studied during admission to P Stra-dins Hospital from 1993 to 1997. We excludedpatients with systemic immunological disor-ders, neoplasms, suspected brainstem en-cephalitis, neuroborreliosis, severe diabetes, orporphyria. The diagnosis of GBS was accord-ing to standard guidelines23: symmetric pro-gressive motor weakness and areflexia of more

than one limb cresting by 4 weeks. One patientwith GBS had a preceding sore throat, andthroat swab cultures for diphtheria in this andfour other patients with GBS were negative.Three patients with GBS were treated withIVIg and 11 with plasma exchange within thefirst 2 weeks of neurological symptoms.

Definite and probable cases of DP werediagnosed according to World Health Organis-ation (WHO) criteria24 after confirmation oflocalised acute diphtheria (tonsillar, palatal,pharyngeal, nasal, lingual, or combined) in 48patients who subsequently developed multiplecranial or limb neuropathy within 6 weeks.Twounsuspected additional cases were includedfrom early in the epidemic after developing

diagnostic clinical features of DP. The patientswith DP exhibited acute laryngitis, nasophar-yngitis, or tonsillitis with pseudomembranesand were defined as having severe toxicdiphtheria if there was neck oedema, toxic col-lapse, acute renal failure, or myocarditis. Toxi-genic strains of Corynebacterium diphtheriaewere isolated from throat swabs in 38 patients.Increased titres of diphtheria antibodies inserum samples were detected in seven otherpatients. Another five patients were diagnosedas clinically probable cases including two withtypical necropsy findings.

CLINICAL ASSESSMENT

Leg weakness and disability were related to aseven point functional scale25 26: 0=normal; 1=minor symptoms and signs but capable of workmanually; 2=able to walk 10 m withoutsupport but incapable of manual work; 3=ableto walk >10 m with a stick or support;4=unable to walk 10 m even with support;5=requiring assisted ventilation; 6=dead. Bul-bar function was expressed on a four pointscale: 0=normal; 1=minor symptoms withoutdysphagia; 2=moderate dysphagia, nasal voice,or palatal paresis; 3=severe dysphagia requiringa nasogastric tube. Ocular motor and facialparalyses were graduated as: 0=normal;

1=minimal symptoms or signs; 2=severe pare-sis or paralysis. Sensory symptoms weregraded: 0=none; 1=minor without aVectingmovement, mood, or sleep; 2=intrusive andneeding symptomatic therapy. Respiratorymuscle function was graded: 0=normal;1=mild to moderate dyspnoea without requir-ing assisted ventilation; 2=needing assistedventilation. A global estimate of the degree ofseverity of each patients neuropathy was

derived. Group I (mild) patients had 0 to 2 legmotor function, or grade 0 to 1 bulbarfunction, or grade 0 to 1 of sensory symptoms,and grade 0 respiratory function. Group II(moderately severe) patients had g rade 3 legmotor function, or grade 2 bulbar function, orgrade 1 or 2 sensation, or grade 1 respiratoryfunction. Group III (severe) patients had grade4 or 5 leg motor function, or grade 3 bulbarfunction, or grade 2 sensation, or grade 2respiratory function. This grading system pro-vides a broad comparison of patients with dif-ferent patterns of neurological involvement,but cannot equally weight diVerent regionaldistributions of involvement.

Neurological assessment was performed onneurological admission, weekly during admis-sion to hospital, and on discharge. Fifteenpatients with GBS and 41 patients with DPwere reassessed after discharge after intervalsof 6 to 18 months: 34 by re-examination, 17 bypostal questionnaire, and five by reports fromother neurologists in outlying regions.

ELECTROPHYSIOLOGICAL STUDIES

Forty one electrophysiological studies in 37patients with DP and 20 in 19 patients withGBS were performed at various stages ofparalysis. Distal motor latencies (DMLs) andmotor conduction velocities (MCVs) in themedian, ulnar, tibial, and peroneal nerves were

measured using a Neuropack-II (Nihon Koh-den, Japan). Normal values for DMLs were4.4,3.4,and 5.8 ms in median, ulnar,and tibialnerves. Normal MCV exceeded 45 m/s in thearms and 40 m/s in the peroneal nerve.

ResultsPATIENT PROFILE

Eighty per cent of patients with DP were aged41 to 60 years and most (84%) were urbandwellers. Many patients with GBS wereyounger, with 52% from rural populations.Fifty two per cent of patients with DP and 71%of patients with GBS were male. Nine (43%) of

the patients with GBS reported antecedentevents between 9 to 30 days (mean 23) beforetheir first neuropathic symptoms, nasal catarrhin eight, sore throat alone in one, whichresolved before onset of neuropathy. None haddiphtheritic pseudomembrane in the pharynxand all five tested patients were negative onthroat swab culture for C diphtheriae. In the DPgroup occurrence of neurological complica-tions was related to the severity of thediphtheritic infection. Thirty patients (60%)had severe forms of diphtheria with systemictoxicity and neck oedema. Seventeen (34%)did not receive diphtheritic antitoxin because

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they consulted late, including nine (18%) who

first presented with polyneuropathy.

COURSE OF DISEASE

The neurological manifestations of DP andGBS generally developed in diVerent se-quences. Typically DP developed over twophases. The first DP symptom was bulbar in 49patients a median of 10 (range 250) days afteronset of localised throat diphtheria. Initialimprovement of bulbar symptoms occurred at30 (range 398) days after onset of neurologi-cal symptoms. In 19 secondary deterioration ofbulbar function occurred 40 (range 1754)days from onset. In 14 others limb symptomseither commenced or worsened while thebulbar symptoms were already recovering.Limb symptoms occurred in 45 patients withDP and appeared at 37 (range 1263) days;limb symptoms never preceded bulbar symp-toms except in one patient with limb involve-ment alone. Peak severity of DP was reached49 (range 1583) days after onset of diphtheriaand improvement began at 73 (range 20115)days. By contrast, neurological deterioration inGBS peaked at 10 (range 228) days, improvedat 21 (range 449) days, and always followed amonophasic course. By contrast DP wasbiphasic in 33 patients, with four requiringintubation and ventilation during the second-ary phase only.

ADMINISTRATION OF DIPHTHERITIC ANTITOXIN

The relation of antitoxin administration (horsehyperimmune serum) to the severity of DP wasanalysed (table 1). Seventeen (34%) patientswith DP did not receive antitoxin, because theyconsulted beyond 1 week from the onset ofdiphtheria and could represent a group withinitially less acutely toxic diphtheria. Five(10%) received antitoxin within 2 days ofonset, and 28 (59%) on the 3rd to the 6th day.In those who received antitoxin early (first 2days) there were no deaths, but two of fivepatients became severely weakened at peakseverity. The rates of death and peak severitywere closely similar in the group not receivingantitoxin, and in those receiving antitoxin 3 to6 days into diphtheria.

CLINICAL FEATURES AT TIME OF MAXIMUM

SEVERITY

Limb weakness was present in all patients withGBS, and 91% of them became unable to walkunaided (table 2). Twelve per cent of patientswith DP developed no limb weakness, and only48% of patients with DP became unable towalk unaided. Achilles tendon reflexes werelost in 78% patients with DP, usually beingretained in those with pure bulbar involvement.Bulbar paralysis aVected 98% of patients with

DP with 32% requiring nasogastric tube nutri-tion. By contrast only 10% of patients withGBS had bulbar dysfunction. Facial paresisand limb sensory disturbances occurred simi-larly in both DP and GBS. Twenty per cent ofpatients with DP required artificial ventilationfor an average of 27 (range 364) days andanother 10% had milder respiratory muscleweakness. Only one patient with GBS had mildrespiratory disturbance and none in this series

required ventilation. Although 36% of patientswith DP showed blood pressure swings or car-diac arrhythmia, autonomic neuropathy couldnot be distinguished from diphtheritic cardio-myopathy. Disturbed bladder function oc-curred in 34% of patients with DP but only 5%of patients with GBS. Six per cent of patientswith DP had visual disturbance due to opticnerve lesions with impaired visual acuity, paleoptic discs, and delayed visual evoked poten-tials. Protein concentrations in CSF wereincreased (>0.45 g/l) in nine of 18 patients withGBS and all six patients with DP (mean 0.8g/l).

Grade 1 (mild) peak severity was more com-

mon in DP (table 2) but grade III severity wasequally common in DP and GBS. All of thepatients with severe DP had initial severelytoxic local diphtheria and only two hadreceived diphtheria antitoxin during the first 2days. All 21 severely aVected patients with DPhad failure of other organs. Sixty four per centof patients with DP had clinical or electro-physiological evidence of myocarditis, 38% hadpneumonia, and 6% had thromboembolism.Organ failure was not a feature of the patientswith GBS.

MOTOR NERVE CONDUCTION STUDIES

Distal motor latencies (DMLs) were similarlyprolonged in DP and GBS at all stages of the

diseases (table 3). Motor nerve conductionvelocities (MCVs) were less markedly slowed,particularly in the early part of the clinical

Table 1 Administration of antitoxin and peak severity of diphtheria polyneuropathy

Day of antitoxinadministration

Total No ofpatients Deaths

SevereDisability(grade III)

ModerateDisability(grade II)

Mild disa bility(grade I)

1st-2nd 5 (100%) 0 (0) 2 (40) 0 (0) 3 (60)3rd-6th 28 (100%) 5 (18) 7 (25) 5 (18) 11 (39)Did not receive 17 (100%) 3 (18) 4 (24) 4 (24) 6 (35)

Data are No of patients (%).

Table 2 Neurological signs at peak severity

GBS (n=21)n (%)

DP (n=50)n (%)

Limb weakness:Mild Grade 1 0 (0) 9 (18)

Grade 2 2 (10) 8 (16)Moderate Grade 3 9 (43) 7 (14)Severe Grade 4 10 (48) 10 (20)

Grade 5 0 (0) 7 (14)Grade 6 0 (0) 3 (6)

Bulbar dysfunction:Mild Grade 1 1 (5) 12 (24)Moderate Grade 2 1 (5) 21 (42)Severe Grade 3 0 (0) 16 (32)

Ocular motor paralysis:Mild Grade 1 1 (5) 10 (20)Severe Grade 2 0 (0) 5 (10)

Facial paresis:Mild Grade 1 4 (19) 5 (10)Severe Grade 2 0 (0) 0 (0)

Respiratory muscle weakness:Mild Grade 1 1 (5) 5 (10)Severe Grade 2 0 (0) 10 (20)

Sensory symptoms:Mild Grade 1 8 (38) 19 (38)Severe Grade 2 2 (48) 23 (46)

Autonomic involvement:Cardiovascular 3 (14) 18 (36)Bladder 1 (5) 17 (34)

GBS=Guillain-Barr syndrome; DP=diphtheria polyneuropa-thy.

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course of DP and GBS, and slowing tended topersist during recovery. Prolonged mediannerve DMLs and slowed MCVs were presentin some patients more than 100 days afteronset of DP and after 1.5 years in one patient.

OUTCOME

For both DP and GBS the proportion ofpatients with only mild manifestations (gradeI) had increased considerably by dischargefrom hospital and correspondingly, the num-bers with severe manifestations (grade III) had

decreased, but more so in the GBS group(table 4). At the time of discharge 10 (24%)surviving patients with DP were unable to walkindependently, compared with 13 (62%) pa-tients with GBS. The average duration of hos-pital admissions for DP was 34.4 (range7101) days and for GBS 19.9 (range 833)days. Follow up at 1 year was possible in 15patients with GBS and 34 patients with DP,both showing further improvement. However,three (20%) patients with GBS and 14 (41%)patients with DP were not able to return tomanual work although able to walk. For thosefollowed up at 1 year, two (6%) survivingpatients with DP and two (13%) patients withGBS still required walking aids. Other limb

symptoms (numbness, paraesthesias, weak-ness) continued after 1 year in 80% of patientswith DP. Eight (16%) of the patients with DPdied, seven while in hospital, on average 70(range 2993) days from the onset of diphthe-ria. Deaths were attributed to cardiac arrhyth-mias (four) after exertion, and to severe septiccomplications (four) variously combined withpneumonia, renal failure, myocarditis, and pul-monary embolism.

DiscussionDiphtheritic polyneuropathy in Latvia aVectedmales and females equally, was most prevalentin urban dwellers aged 40 to 60 years, and nopatients with DP were encountered aged under18 years. This population of 50 patients withDP studied at a neurological centre in Riga canbe related to the overall diphtheria epidemic inLatvia. They comprise about half of all knownpatients with DP in Latvia during this period.15

Data from the National Environmental HealthCentre registered 731 cases of diphtheria inLatvia in 19946, 57% adults aged 3050.During this period in the whole of Latvia weare aware of a total of 111 patients with DP.Thus at least 15.2% of all patients diagnosedwith diphtheria developed polyneuropathy.Polyneuropathy is generally regarded as beinguncommon in mild diphtheritic infection, butoccurs in about 10% of cases of average sever-ity and in up to 75% of severe cases.3 Ourpresent day Latvian data confirm that polyneu-ropathy is far more likely to develop after severelocalised diphtheritic infection, including bullneck and those with toxic shock.2 3 27 28

Immediate administration of horse serumantitoxin has been regarded as a mainstay ofdiphtheria treatment after its introduction in1894,10 but it is unclear for how long after theonset of diphtheria infection such treatmentwill be still beneficial.24 Serum sickness canoccur in up to 10%.3 No formal clinical trials ofantitoxin administration have been performed,but the incidence of paralysis only seems to bereduced if antitoxin is administered during thefirst 2 or 3 days of diphtheritic infection.4 10

Our contemporary retrospective data also pro-vide no evidence that antitoxin administeredafter day 2 of infection modified the severity ofneuropathy or prevented deaths. Our data sug-gest that antitoxin administration on days 02

prevents death although cases of severe neu-ropathy still occur.

The main clinical features of diphtheriticpolyneuropathy described in present daytexts2 3 29 30 followed experience during the epi-demics at the turn of the century and duringthe second world war.46 10 Recent descriptionsof DP are based on single cases or smallnumbers.11 3133 Our analysis of 50 patients withcontemporaneous DP shows that bulbar andrespiratory involvement continue to predomi-nate, in 98% and 30% of patients respectively.Present day endotracheal intubation, assistedventilation, and nasogastric tube feeding en-sure greater survival and were required in 32%

of our patients with DP. Although 16% of ourpatients with DP died, this was not usually adirect consequence of bulbar or respiratorymuscle failure. There are no estimates of respi-ratory failure in diphtheritic polyneuropathybefore the introduction of endotracheal ventila-tion and the overall death rate of 2%-4% 4 indiphtheritic infection doubtless included manynon-neuropathic complications. Optic neu-ropathy, occurring in three (6%) of ourpatients, is not a generally recognised feature ofDP, but such visual disturbances have beendescribed previously.10 Nerve conduction stud-ies were not available to study earlier epidemics

Table 3 Motor Nerve conduction studies

Nerve PhaseNo ofpatients

DP (meanDML (SD))

No ofpatients

GBS (meanDML (SD))

Median nerve Evolution 3 5.2 (0.35) 3 5.5 (0.5)Plateau 6 6.5 (1.4) 5 6.8 (0.9)Recovery 32 5.8 (0.2) 15 5.9 (0.3)

Ulnar nerve Evolution 3 4.0 (0.2) 3 3.6 (0.3)Plateau 6 4.0 (0.4) 5 4.8 (0.6)Recovery 32 4.2 (0.1) 12 4.1 (0.2)

Tibial nerve Evolution 3 6.8 (0.3) 3 6.2 (0.8)Plateau 6 8.6 (1.5) 5 8.5 (0.8)

Pecovery 32 2.5 (0.3) 15 8.5 (0.6)

GBS=Guillain-Barr syndrome; DP=diphtheria polyneuropathy; DML=distal motor latency.

Table 4 Outcome at discharge, and at 1 year

GBS n (%) DP n (%)

Peak severity 21 (100) 50 (100)

Grade 1 2 (10) 20 (40)Grade 2 9 (42) 9 (18)Grade 3* 10 (48) 16 (32)Death 0 (0) 5 (10)

At discharge 21 (100) 45 (100)Grade 1 8 (38) 33 (73)Grade 2 12 (57) 2 (4)Grade 3* 1 (5) 8 (18)New deaths 0 (0) 2 (4)

At 1 year 15 (100) 34 (100)Grade 1 13 (87) 31 (91)Grade 2 2 (13) 2 (6)Grade 3* 0 (0) 0 (0)New deaths 0 (0) 1 (3)

GBS=Guillain-Barr syndrome; DP=diphtheria polyneuropa-thy.*Grade 3 excludes deaths.

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of DP. A few electrophysiological studies havebeen reported more recently, generally showingreduced motor nerve conduction velocity,initially mild, and still decreasing while clinicalrecovery begins.9 12 34 Our data confirm thesefindings and did not disclose any electrodiag-nostic diVerences between DP and GBS.

A novel finding was of a secondary deteriora-tion in DP symptoms in 66%. In 38% the bul-bar symptoms deteriorated afresh after initial

partial recovery, and ventilation first becamenecessary during this second bulbar phase insome. In 28%, limb symptoms started or con-tinued to worsen while bulbar symptoms hadstarted recovering. This biphasic fluctuation inthe course of disease suggests that diphtheriatoxin locally aVects nerve endings in bulbarmuscles at an early stage, before systemicdispersion of the toxin produces late eVects onlimb or bulbar nerves. In 10% of patients withDP with bulbar paralysis there were no limbsymptoms and Achilles tendon jerks were pre-served; no secondary deterioration occurredand we suspect that these patients exhibited thelocal bulbar eVects of diphtheria toxin without

any significant systemic dispersion.The particular clinical features diVerentiat-ing DP from GBS are fir stly the highprevalence of bulbar and respiratory muscledysfunction at a time of little or no limbinvolvement; secondly, the evolution of theneuropathy for much longer than 4 weeks;thirdly, the preceding sore throat rather thancatarrhal illness; and fourthly, the simultaneousinvolvement of other organ systems. Both causesimilar patterns of limb involvement. Most DPstarted within the first 2 weeks after localinfection, a similar time interval to thatseparating GBS from its antecedent infections.Our 21 patients with GBS showed less frequentfacial, bulbar, respiratory, and ocular motor

involvement, commoner sensory disturbance,were generally younger than in larger series,and none died.2 21 22 3538 The initial diVerentialdiagnosis from GBS is diYcult for those occa-sional patients with DP without bulbar palsy.Basically, DP limb symptoms evolve for longerthan GBS, last longer, and are more likely toresult in chronic disability; only 20% werecompletely healthy after 1 year.35 38 At 1 year6% of our patients with DP and 13% ofpatients with GBS were unable to walkindependently; previous series show that 16%of patients with GBS cannot walk independ-ently at 1 year.39 Of those we were able to followup, 20% of patients with GBS and 41% of

patients with DP had been unable to return tomanual work; but we cannot discriminatebetween those incapable of manual work andthose whose illness had simply transferredthem to the unemployment register.

Toxic failure of systemic organs is the majorinfluence on survival from diphtheria now thatendotracheal intubation prevents death due tobulbar or respiratory muscle failure. Half totwo thirds have evidence of cardiac dysfunc-tion, clinically apparent myocarditis developsin 10%-25%, and pneumonia occurs in morethan half of fatal cases of diphtheria.3 Combi-nations of DP and myocarditis were frequent,

occurring in 64% of our patients, and nephritis(18%) and pneumonia (38%) were alsocommon. We confirmed that diphtheritic myo-carditis is the major cause of death indiphtheria41 42 and severe pulmonary complica-tions are also found, particularly in adults.43 Itcan be diYcult to discriminate between theautonomic cardiovascular disturbances in DPand the myocarditis. Mortality from diphtheriagenerally increases with severity of local disease

and if antitoxin is not administered immedi-ately after the onset of local disease. Our studyshowed a mortality of 16% in DP, reflecting theinitial severity of local diphtheria. The deathrate is highest among patients with bull neckdiphtheria or other toxic forms, which are pre-dictors of cardiac, neuropathic, or othercomplications.1 3 24 28 29 4345 The overall casefatality rate for diphtheria was 2.4% in the1940s4 and remained at 2%-3% in the Russianoutbreak of the 1990s.1

We thank Mrs E Vesma and Mrs J Wilkinson for preparing themanuscript,Dr I Kravale for the neurophysiological studies, andthe British Council for a travel grant.

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