Clinical manifestations

Presentation and course

Diphtheritic neuropathy classically follows primary diphtheria infection, which usually involves tonsils, pharynx, and larynx with a characteristic membranous exudates, or skin. The severity of the diphtheritic polyneuropathy is also related to the severity of the diphtheria infection. Sixty percent of patients with diphtheritic polyneuropathy had a preceding severe diphtheria infection with cardiac and renal impairment (23). Young adults with diphtheria were reported with palatal paralysis in 15% and polyneuropathy in 11% of cases observed during the Second World War (32). A 15% incidence of neurologic complications was reported in adults from age 41 years to 60 years (23). In children, the incidence of diphtheritic polyneuropathy was reported 20% to 27% at the turn of the century (38). Recent pediatric cases of diphtheritic polyneuropathy were reported: palatal palsy in 44% to 64%, and limb muscle weakness in 22% to 94% (19; 25; 35; 14; 16).

Piradov and colleagues reported that the latency in development of diphtheritic polyneuropathy varies from 18 to 46 days after the initial infection (33). In children, diphtheritic polyneuropathy occurred 5 to 36 days after the onset of diphtheria infection (14; 16). Neurologic manifestations of diphtheria are biphasic, characteristically producing early bulbar disturbance and late motor weakness in the truck and extremities. Improvement in cranial nerves occurs with evolving motor disturbance in the trunk and extremities. Krumina and colleagues found that patients vaccinated against diphtheria developed mild limb polyneuropathy of later onset, with a median onset of 43 days (range 35 to 58), and less prominent early bulbar features (21).

The disturbance of cranial nerves IX, X (100%), VII (88%), III, IV, VI, XI (84%), XII (72%), and V (53%) were most frequently observed during weeks three through five of initial diphtheria in Piradov’s group (33). The symptoms are numbness in gingivae, tongue, and face, nasal speech, nasal regurgitation, difficulty in reading, diplopia, dysphonia, and dysphagia. Physical examination reveals accommodation, convergence or papillary light reflex disturbance, anisocoria, ptosis, mydriasis, palate paralysis, laryngeal paralysis or spasm, and weakness sternocleidomastoid muscles and tongue (22).

Generalized peripheral neuropathy usually appears in five to eight weeks. Maximal weakness was reported on day 51+10 days in Piradov’s group (33). Weakness is usually in proximal or distal limbs followed by atrophy in severe cases. Hypotonia and gait abnormality are also found. Paralysis of the diaphragm and respiratory muscles were observed, requiring mechanical ventilation from 17 to 62 days. Patients have sensory disturbances in all modalities with numbness, paresthesia of distal extremities, and sensory ataxia. Tendon reflexes are depressed or absent. Plantar responses are typically flexor (39; 40; 37).

Autonomic disturbance is present in diphtheritic polyneuropathy, with the incidence ranging from 36% to 100% in severe diphtheritic polyneuropathy as reported from different authors. Autonomic neuropathy produces prominent abnormalities of parasympathetic reflexes and normal sympathetic function (15). Patients may have sinus tachycardia, arterial hypotension, urinary retention, hyperkeratosis and xeroderma, or hyperhidrosis of the face, neck, and chest. It may be difficult to differentiate myocarditis from autonomic instability.

In a review of 50 cases of diphtheritic polyneuropathy, the peak severity was a median of 49 (range 15 to 83 days) days after onset diphtheria and improvement started 73 (range 20 to 115 days) days in Logina and Donaghy’s group (23).

Prognosis and complications

The overall fatality rate of diphtheria was 2.4% in the 1940s and remained 2% to 3% in the outbreak in Russia (36). Mortality increases with severity of local disease and delay in administration of antitoxin. Roche and colleagues reported that antibiotic therapy in combination with antitoxin administration within 48 hours decreases the subsequent development of diphtheritic polyneuropathy by 50% (37). Piradov and colleagues reported an inverse relationship between diphtheritic polyneuropathy latency and neurologic recovery (33). A longer latency was associated with early regression. Systemic organ failure is the most influential factor on survival in diphtheritic polyneuropathy, as death due to bulbar or respiratory failure is preventable by endotracheal intubation and mechanical ventilation. Diphtheritic myocarditis is the major cause of death, and pneumonia occurs in more than half of fatal cases (04). Although pediatric cases presented with severe symptoms, the prognosis was good with duration of recovery 1 to 7 weeks in isolated bulbar palsy, and 6 to 17 weeks with limb paresis (35; 14; 16). In a follow up of 50 patients with diphtheritic polyneuropathy, Logina and Donaghy found the average duration of hospitalization to be 34.4 (range 7 to 101 days) days (23). Of this group, eight patients (16%) died, with four deaths due to cardiac arrhythmias, and four deaths from severe septic complications. Follow-up at one year in 34 of these patients found 14 (41%) unable to return to manual work but able to walk, whereas two (6%) required walking aid, and 80% still continued to have limb paresthesia, numbness, and weakness. In Piradov’s group, there was a complete recovery in 30 out of 32 patients. Two patients died because of pneumonia and acute cardiovascular insufficiency (33).

Biological basis

Etiology and pathogenesis

Diphtheria neuropathy is an acute toxin-mediated disease caused by Corynebacterium diphtheriae. C diphtheriae is an aerobic gram-positive bacillus. Three biotypes (mitis, intermedius and gravis) are capable of causing diphtheria. They are differentiated by colonial morphology and hemolysis as well as fermentation reactions (17). C diphtheriae exclusively resides in the mucous membrane and skin of humans. Diphtheria spreads via airborne respiratory droplets or direct contact with respiratory secretions of symptomatic individuals or infected skin lesions. Asymptomatic carriers are also important in transmission.

Diphtheritic neuropathy is characterized by paranodal demyelination, and segmental demyelination at ventral and dorsal spinal roots or peripheral nerves. Axonal continuity is usually preserved, but occasionally there might be complete degeneration resulting in destruction of axon and myelin (10; 24; 26; 35). C diphtheriae produces a 62-kd polypeptide exotoxin, which inhibits protein synthesis and causes local tissue necrosis. The toxin is comprised of two subunits. Fragment-B facilitates the entry of fragment-A into cells. Fragment-A catalyzes the transfer of an adenosine diphosphoribose component of the nicotinamide adenine dinucleotide molecule to elongation factor-2, and thereby inhibits protein synthesis. The covalent linking of factor-2 to adenosine diphosphoribose renders it nonfunctional and leads to subsequent disruption of protein synthesis, causing cell necrosis (18). Pleasure and colleagues found that diphtheria toxin does not increase the degradation of myelin lipid or proteins, but the toxin inhibits the synthesis of myelin proteolipid and other basic proteins, leading to a demyelinating neuropathy (34). Toxin absorption also causes local tissue necrosis, kidney tubules necrosis, thrombocytopenia, and cardiomyopathy. The biphasic clinical presentation may be explained by early bulbar disturbance through direct toxin spread and late motor disturbance in the trunk and extremities from hematogenous dissemination (27).

Epidemiology

Diphtheria was a dreaded, highly endemic childhood disease found in temperate climates. In the early twentieth century, it was one of the leading causes of death in children. The introduction of routine immunization with diphtheria toxoids in the 1940s and 1950s led to a dramatic reduction in the industrialized world. In the Unites States, the number of cases has decreased from 60,000 cases in 1932 to five cases in 1982. There were seven outbreaks of diphtheria from 1971 to 1981 in the United States, with high attack rates for American Indians. After 1979, cutaneous diphtheria was no longer tracked. Only 24 cases of diphtheria have been reported from 1980 to 1989 (02). Cases of clinical diphtheria are extremely uncommon. Since the mid-1980s, there has been striking resurgence of diphtheria in several countries in Eastern Europe. In 1993, the World Health Organization received 15,211 diphtheria cases in Russia and 2,987 cases in Ukraine. The main reason for this return was decreased immunization coverage among infants and children, waning immunity in adults, population migration, and irregular vaccine supply (12). Since 1994, aggressive immunization efforts have led to a decrease in reported cases. In India between January 2009 to January 2011, 200 diphtheria cases were reported, and of this number, 150 patients had inadequate immunization (20). The World Health Organization reported a total of 8819 cases of diphtheria worldwide in 2017, the most since 2004. In countries with higher case counts, 66% of case patients were unvaccinated and 63% were younger than 15 years of age (05). There were 5125 diphtheria cases in 2000 and 4233 in 2011 in India (14). In February 2023, 216 confirmed diphtheria cases was found by the Nigeria Centre for Disease Control (01). There is no racial or sexual predilection. Diphtheria has shifted from an endemic affliction of children to a disease of adults due to a lack of natural exposure to toxigenic C diphtheria in the vaccination era or low rates of booster injections. In serosurveys in the United States, Sweden, Italy, and Denmark, 25% to 60% of adults lacked protective antitoxin, especially among the elderly (11). In a report from Sao Paulo, Brazil, 84% of 374 individuals had full protection from diphtheria, 15% had basic protection, and 1% was susceptible to the disease (07).

Prevention

The only measure for effective control against diphtheria is universal immunization with diphtheria toxoid throughout life. This provides constant protective antitoxin levels. Immunization decreases local spreading, decreases the transmission of the organism, and prevents the carriage of toxigenic C diphtheria. The conventionally accepted minimum protective level of serum antitoxin is 0.01 IU/mL with 0.1 IU/mL, providing definite protective level (30). Diphtheria and tetanus toxoid with pertussis are the vaccine of choice for children six weeks through six years. The usual schedule is a primary series of four doses at two months, four months, six months, and 15 to 16 months of age as CDC recommended. If pertussis vaccine is contraindicated, then pediatric diphtheria and tetanus toxoid should be used to complete vaccination. The level of coverage for routine vaccination in low-income and middle-income countries was still under 80% in 2009 (41). Antitoxin levels wane over time. Most individuals have antitoxin levels below optimum levels 10 years after the first dose. In 128 healthy individuals who had been administered at least one dose of the vaccine, 49.2% exhibited only minimal protection against diphtheria, which emphasized the need for periodical booster immunization (09). Tetanus toxoid should be given with diphtheria toxoid every 10 years. Diphtheria disease does not confer immunity and individuals recovering from diphtheria should begin or complete active immunization during convalescence.

Roche and colleagues reported that antibiotic therapy in combination with antitoxin administration within 48 hours decreases the subsequent development of diphtheritic polyneuropathy by 50% (37). The incidence of diphtheritic polyneuropathy seems to be reduced if antitoxin is administered during the first two days of diphtheritic infection. Antitoxin administered after day two does not modify the severity of neuropathy. Diphtheria antitoxin was used in 709 diphtheritic patients of Rohingya refugees in Bangladesh from 2017 to 2018 (08). Out of the patients, 98% of patients recovered from diphtheria, and about 25% of patients had at least one adverse reaction. Common reactions included cough (16%), rash (9%), and itching (5%). Three percent had severe hypersensitivity reactions (08).

Differential diagnosis

Confusing conditions

Guillain-Barre syndrome or acute inflammatory demyelinating polyradiculoneuropathy is typically the presumed initial diagnosis. Diphtheritic polyneuropathy and Guillain-Barre syndrome share similar patterns of limb involvement as well as similar time-frame separation from the preceding infection. The clinical features that distinguish diphtheritic polyneuropathy from Guillain-Barre syndrome are bulbar and respiratory muscle dysfunction at the time of little or no limb involvement, disturbance of accommodation, history of sore throat rather than any catarrhal illness, biphasic pattern of illness, more than four weeks of symptom evolution, and concomitant involvement of other organ systems.

Acute myelopathy is also a consideration. Diminished or absent reflexes can be seen in both disorders, but early bladder or bowel impairment should alert the possibility of acute myelopathy.

Myasthenia gravis is suggested by a history of fatigability, fluctuating symptoms, and the response to anticholinesterase.

Acute botulism should be suspected if weakness follows within 12 to 36 hours of ingestion of tainted food and is associated with dilated, nonreactive pupils.

West Nile virus infection may present with weakness as myelopathy or polyneuropathy, but frequently also with encephalopathy and mental status change.

Lyme disease is a differential diagnosis, but Lyme disease may have a history of tick bite and erythema migrans.

Other differential diagnoses include tick paralysis, meningeal carcinomatosis, paraneoplastic neuropathy, vasculitic neuropathy, heavy metal toxin, acute porphyria, and polymyositis.

Diagnostic workup

Diagnostic workup to confirm infection combines isolation of C diphtheria on culture with toxigenic testing. Nasopharyngeal swab is obtained from the patient and the contacts. Isolation from close contacts may confirm the diagnosis, even if the culture on specimen from the patient is negative. C diphtheria requires special culture median containing tellurite. Elek test is performed to determine if the bacillus produces toxin. As toxigenic testing is not readily available, state health department or CDC may provide information. Measurement of serum antibodies to diphtheria toxin may also help assess the probability of diphtheria. PCR can confirm infection with toxigenic strain but is not commercially available. Clinical samples should be sent to the CDC diphtheria laboratory for testing.

A variety of changes in the CSF in diphtheritic polyneuropathy have been described. Both lymphocytosis and dissociated increase of protein have been recorded. However, there was no parallel between anomalies of CSF and seriousness of clinical signs. In 27 cases with severe diphtheritic polyneuropathy, Piradov and colleagues found increase of CSF pressure from 200 to 440 mm H2O in nine cases (33). The CSF protein was 15 to 283 mg/dl, and the cell count (lymphocytes and neutrophils) was never more than 12 mm3.

Diphtheritic polyneuropathy is characterized by demyelination. Nerve conduction studies show prolongation of distal motor latency, delayed F-wave latency, slowing of conduction velocity, and if severe, conduction block and temporal dispersion (06). There is, however, a dissociation of clinical and electrical findings. The conduction abnormalities are mild, even when limb weakness is marked in the first few weeks (13). The delay in development of conduction abnormality is probably because changes in the peripheral segments of nerves appear later than in the ganglia and roots. Axonal degeneration, possibly secondary to demyelination, was reported in six of nine patients in a recent study (Prasad & Rai 2018). Autonomic tests showed impairment of R-R variation and Valsalva testing. Brainstem auditory evoked potentials may identify auditory nerve impairment (31).

The biopsies of nerves show paranodal and segmental demyelination with preservation of axonal continuity, or axonal degeneration secondary to demyelination in severe cases, and thin myelin sheaths with short internodes (29). Lozhnikova and colleagues found remyelination began after 35 days from onset diphtheria (24). Muscle biopsy showed neurogenic atrophy with no inflammation (40; 06).

Management

There is no specific treatment for diphtheritic polyneuropathy and the management is conservative. Attention must be paid to protect the airway. Decrease in vital capacity of the lungs below 16 ml/kg body weight or paralytic closure of larynx with increasing weakness of the respiratory muscle is an indication for mechanical ventilation. Circulatory collapse is most probable in weeks four to seven of diphtheritic polyneuropathy, requiring hemodynamic monitoring and, if indicated, vasopressors for three to 10 days. Urinary retention may require persistent catheterization for five to 14 days.

Special considerations

Pregnancy

There is no reported case of diphtheritic polyneuropathy during pregnancy.