Year : 2018 | Volume
: 13 | Issue : 3 | Page : 313--316
Prospective study of diphtheria for neurological complications
Prem L Prasad, Preeti L Rai
Department of Paediatrics, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh, India
Dr. Preeti L Rai
A-10, Doctors Residence, Ram Murti Puram, Shri Ram Murti Smarak Institute of Medical Sciences (SRMSIMS), Bhojipura, Bareilly, Uttar Pradesh 243202
Aim: To study the spectrum of neurological complications of diphtheria, timing of onset with respect to respiratory disease, and pattern of recovery. Settings and Design: Prospective, observational, hospital-based study conducted in tertiary care hospital. Materials and Methods: Twenty-eight cases of diphtheria with neurological complications were admitted during the period of study. Demographic profile, age, gender, status of immunization, past history stressing on the severity of the respiratory disease, and complaints regarding diverse complications of diphtheria were recorded. Detailed clinical and central nervous system examinations along with relevant investigations were carried out. Results: Children were in the age group of 3–18 years. All 28 children presented with bulbar symptoms. Isolated palatal palsy was present in 18 children (64%). Third cranial involvement was present in four children. Three children had unilateral lower motor neuron facial palsy and one child had sixth cranial nerve palsy. Nine children developed symmetric limb weakness. Diaphragmatic palsy was present in three children with the onset from 1–3 weeks after pharyngeal diphtheria. Loss of vasomotor tone was present in two children. Recovery was complete` in all 28 children. Conclusion: Pediatricians/neurophysicians should have a high index of suspicion to recognize diphtheritic polyneuropathy. It carries good prognosis, hence timely diagnosis and differentiation from other neuropathies is a prerequisite for rational management and contact tracing.
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Prasad PL, Rai PL. Prospective study of diphtheria for neurological complications.J Pediatr Neurosci 2018;13:313-316
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Prasad PL, Rai PL. Prospective study of diphtheria for neurological complications. J Pediatr Neurosci [serial online] 2018 [cited 2022 Sep 25 ];13:313-316
Available from: https://www.pediatricneurosciences.com/text.asp?2018/13/3/313/240770
Diphtheria still remains one of the most common infectious diseases encountered in unimmunized and partially immunized population. Twenty thousand cases of diphtheria were reported by the World Health Organization during 2007–2011, of which 17,926 cases (89.6%) were from India alone and this was more than all other highest reporting countries combined. Poor immunization coverage is the main factor for the persistence of diphtheria. National Family Health Survey-3 found only 43.5% children between the ages of 12 and 23 months fully immunized nationwide, and immunization coverage was as low as 30% in Uttar Pradesh, India. There is also tremendous heterogeneity in state- and district-level immunization in the country.
Diphtheria and its neurological complications are almost a forgotten entity by present day physicians because the disease is confined only in some parts of the country where immunization coverage is low. Neurological involvement is recognized as one of the most severe complications of diphtheria. Neurological complications parallel the severity of primary infection and are multiphasic in onset. Exotoxin of Corynebacterium diphtheriae is responsible for the neurological manifestations. Literature on neurological complications of diphtheria is scarce. Low index of suspicion, underrecognition, and underreporting are the main concerns. Only two case series are reported till date in India.,
A prospective, observational, hospital-based study was carried out on 42 cases of membranous tonsillitis, which were admitted in our hospital from August 2014 to January 2016. Among these, only 39 cases were diagnosed as diphtheria.,, Nine cases expired during the phase of the respiratory disease because of severe toxicity. Remaining 30 children were treated with antidiphtheritic serum (ADS), antibiotics, and supportive treatment. Two cases had mild respiratory disease and 28 cases required tracheostomy because of severe respiratory embarrassment. These 30 cases were followed up for neurological complications. Of 30 cases, only 28 came with neurological complications. Thus, in total 28 children were chosen for the study.
Demographic profile, age, gender, status of immunization, past history stressing the severity of the respiratory disease, and complaints regarding diverse complications of diphtheria were recorded. Detailed clinical and central nervous system examinations were carried out. Investigations such as cerebrospinal fluid (CSF) analysis, nerve conduction velocity (NCV), and magnetic resonance imaging were carried out, wherever required. All 28 children had one or many neurological complications of diphtheria with spectrum from mild to severe presenting at different periods of follow-up.
Children in this study were in the age group of 3–18 years (mean, 6.9 years, 22 boys and 6 girls). Eighteen children were not immunized at all and 10 were partially immunized. All the children had history of membranous tonsillitis with severe respiratory obstructions. A latent period of 4–49 days was observed between the onset of membranous tonsillitis and neurological complications. Isolated palatal palsy was present in 18 children (64%). Bulbar symptoms in the form of nasal twang, regurgitation, and dysphagia were observed in all children. Third cranial nerve involvement manifested by ptosis, anisocoria, and diplopia was present in four children. Three children had unilateral lower motor neuron facial palsy and one child had sixth cranial nerve palsy. Nine children developed symmetric limb weakness. Ascending paralysis was noted in seven cases (25%), whereas descending in two cases (7%). Majority of patients had hyporeflexia or areflexia (88.9%) and hypotonia. Sensory symptoms in the form of paresthesia, hypesthesia, and hyperesthesia were present in all cases (100%). Diaphragmatic palsy (DP) was present in three children within 1–3 weeks after pharyngeal diphtheria and required mechanical ventilation. Loss of vasomotor tone was present in two children (7%) who required vasopressor support.
NCV was performed in nine patients; six had axonal degeneration secondary to demyelination and two had acute demyelination. All the children were given Ryle’s tube feeding ranging from 1 to 6 weeks along with supportive and symptomatic treatment. Recovery was complete in all 28 children.
Duration of recovery was 1–5 weeks in case of isolated bulbar palsy, whereas it was 10–15 weeks in children with quadriparesis and around 5 weeks in DP. Nine children died within 1 week from the onset of respiratory disease because of severe toxicity.
Table showing summary of neurological complications of diphtheria is as follows:
There has been reemergence of diphtheria among children, adolescents, and adults in many states. Toxigenic strains of C. diphtheriae release a toxin that has a local effect of a pseudomembrane formation in the pharynx, larynx, and nasal cavity. The toxin also results in systemic toxicity, myocarditis, and neurological complications. Paralyses of the muscles of pharynx, larynx, and diaphragm are early manifestations of the disease and manifest in the first few days.
Diphtheria is no more a disease of children under 5 years, but unimmunized and partially immunized children are more at risk because of waning of immunity of primary immunization. Serological survey in the US has shown decreased immunity against diphtheria in 20%–50% of cases among adults and adolescents. In outbreaks also, more adolescents and adults were found to have diphtheria. In India and many other countries, cases of diphtheria have shown comeback because of waning of immunity. Majority of cases in our study were around the average age of 7 years (3–18 years) and approximately 40% were partially immunized. Jain et al. found diphtheria in 54% of unimmunized children. It was commonly seen in male patients and during the months July to September.
The clinical course of diphtheria depends on the severity of symptoms because of the extent of membrane and also the amount of toxin absorbed by Schwann cells. It inhibits the synthesis of myelin and leads to neurological symptoms. Neurological complications have been observed in 15%–27% cases of diphtheria. Neurological complications were seen in 20% of patients with mild respiratory diphtheria versus 75% of patients with severe respiratory disease in a study conducted by Hadfield et al. We found that all 28 children (100%) with severe respiratory disease developed neurological complications in our series. This can be attributed to our hospital being a tertiary care hospital; many cases reached us quite late and even without antitoxin.
Diphtheritic polyneuropathy is recognized as one of the most severe complications of diphtheria caused by exotoxin of C. diphtheriae. The term “diphtheritic polyneuropathy” encompasses all neurological symptoms with the onset of palatal paralysis as the first symptom. Palatal paralysis is a very common neurological complication, which may occur alone or in association with bulbar palsy. Isolated palatal palsy was present in 18 cases (64%) in our study. Manikyamba et al. reported isolated palatal palsy in 56% cases. Mateen et al. found palatal palsy only in 13% cases. The onset of neurological complications in our series was seen from 4 to 49 days (median, 18 days) after respiratory symptoms. Similarly, in the Latvian study of 50 adult patients with diphtheritic paralysis, neurological complications appeared in 2–50 days (median, 10 days) after the onset of respiratory diphtheria. It was a bit early in our series as compared to other studies in which a latent period between the appearance of first symptom of diphtheria and the development of palatal palsy varied from 10 days to 3 months. This could be attributed to the severity of diphtheria at the time of presentation.
Bulbar palsy was seen in all 28 cases in our series and the onset ranged from 2 to 5 weeks. These symptoms typically develop during the first 2 weeks and vary from mild to severe and are seen in almost all patients with diphtheritic polyneuropathy.,
The involvement of cranial nerves has also been reported in diphtheria cases. Oculomotor nerve involvement was found in four cases (14.28%) in our study. Besides third cranial nerve, facial weakness was also observed in only three cases (11%). Manikyamba et al. also found oculomotor nerve involvement only in three cases (15%). Piradov et al. found it in 84% of patients and Logina and Donaghy observed it in 30%, which is contradictory to our study.
Neurological involvement has been observed in two phases. Symmetric polyneuropathy in trunk and extremities was noted 4–9 weeks after the onset of pharyngeal diphtheria. This was also accompanied by functional recovery in bulbar palsy and cranial nerves. Bulbar palsy started to recover around 4–9 weeks in our study. Other workers have also found limb symptoms typically around 5–8 weeks after the onset of pharyngeal diphtheria. These authors also noted that the recovery of cranial nerves was accompanied by worsening of motor weakness of the trunk and extremities during the 2nd month of disease.,,,
We observed symmetric motor weakness in trunk and extremities in nine cases (32%). Of these nine cases, only two (22%) had weakness of descending type, whereas the rest seven (78%) had ascending paralysis. The study by Mateen et al. showed that paralysis was ascending in 33%, descending in 27%, and uncertain in 40% cases, but was most often symmetric. Contradictory to our study, descending quadriparesis was seen in 60%–90% of patients with diphtheritic polyneuropathy in another study, which is much greater than that of in our study.
Classically, diphtheritic polyneuropathy is considered to be a pure demyelinating disease with sparing of the axons. Of the nine cases, only two (22%) had demyelinating disease in this study and seven (78%) had axonal degeneration. Not many references showing axonal neuropathy in diphtheria are available. Histological studies have shown that affected nerves have significant degeneration of myelin sheaths and axons. Axonal damage is secondary to the application of external pressure from swollen neurons. Axonal continuity is usually maintained but occasionally complete degeneration resulting in destruction of axon and myelin might be observed. Axonal degeneration is observed in most severe cases and appears secondary to the axon being squeezed by folded myelin and voluminous Schwann cell cytoplasm invaginating into the axon. There is increasing suggestion in experimental studies that axonal function is also affected with a loss of sensory neurons and motor axons.
In our study, recovery from motor weakness started from 14 to 22 weeks after the onset of pharyngeal diphtheria or 2–4 months after the onset of neuropathic symptoms and was complete. Other studies had similar results.,
Autonomic dysfunction in the form of loss of vasomotor tone is also a complication of diphtheria. Only two cases presented with the loss of vasomotor tone in our study, which manifested as tachycardia, arrhythmias, and arterial hypotension requiring vasopressor support for approximately 3–4 weeks after throat diphtheria. In contrast, the study by Logina and Donaghy found autonomic dysfunction to be a common complication of diphtheria.
Three patients in this study presented with DP and two required mechanical ventilation in contrast to the study from Delhi where respiratory muscles were involved in 85.4% cases and 60.4% required mechanical ventilation. Respiratory embarrassment was managed by timely tracheostomy.
CSF studies may be normal or show elevated protein levels (albumin-cytologic dissociation). CSF analysis was carried out in seven cases; CSF was normal in four cases and three cases had elevated protein levels in this study. In a study by Mateen et al., the results were within reference ranges for all patients. Contrary to this, Manikyamba et al. reported elevated protein levels in majority of the patients.
Mortality from diphtheria varies from 8% to 46% in various studies. In this study, only nine cases (32%) died.
Pediatricians should have a high index of suspicion to recognize diphtheritic polyneuropathy in the wake of recent resurgence of diphtheria in some parts of India. Any child diagnosed with probable diphtheria should be promptly treated with ADS and followed up for 3–6 months for neurological complications. As seen in our case series, diphtheritic polyneuropathy carries good prognosis, hence timely diagnosis and differentiation from other neuropathies is a prerequisite for rational management and contact tracing.
Diphtheria is a vaccine-preventable disease. Continued occurrence of diphtheria emphasizes the need for public health measures such as strengthening of routine immunization along with adequate cold chain maintenance, emphasis on booster vaccination at school entry, and tetanus toxoid and low dose diphtheria toxoid vaccine/ tetanus toxoid, low dose diphtheria toxoid and acellular pertusis vaccine booster at regular intervals of 10 years. Vaccinations and prophylactic antibiotics to susceptible contacts should also be a priority.
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