Typhoid (enteric) fever is a bacterial disease caused by Salmonella enterica serovar Typhi (S. Typhi). It is one of the critical causes resulting in maximum morbidity and mortality. As reported by John, VanArt, and Grassly [1], the global burden of disease in India in 2010 was estimated to be approximately 12 million. The global fatality rate of this disease is around 1%, leading to annual deaths of almost 1, 30, 000 affected individuals. The incidence was found to be highest in the age range of 2-4 years. Developing countries like India face a greater challenge of Typhoid, especially when the disease is multi-drug resistant. Public health intervention measures like infant immunization using typhoid conjugate vaccines can resolve this threat. Though WHO recommended the use of vaccines to control this endemic disease, in India, it is not included in the National Immunization Schedule. Indian Academy of Pediatrics also recommended the inclusion of the typhoid conjugate vaccine at 9-12 months of age, followed by a booster dose at two years of age. Typhoid is transmitted via the faecal-oral route due to contaminated water or food intake. Few risk factors causing this disease include poor sanitation, lack of pure drinking water, low socioeconomic status and inadequate hygiene practices. Therefore, the burden of the disease is variable within and across countries. The most common signs and symptoms of the disease include headache, abdominal pain, constipation, diarrhoea, and malaise. A few cases also reported severe complications such as hepatitis, pneumonia, intestinal perforation and tissue abscesses. Neurologic manifestations such as meningitis and encephalitis are also associated with this disease. Other neurological signs, though in few cases, include spasticity and clones, acute neuropsychiatric illness, ataxia, aphasia, and cerebritis. Ali et al. [2] studied the neuropsychiatric complications in 791 individuals with Typhoid in India and reported acute confusion as the most common manifestation (76%). Another manifestation being myelitis (6.32%), cerebellitis (1.26%), Parkinsonism (1.01%), acute psychosis (0.63%), meningoencephalitis (0.50%), encephalitis (0.25%), sensorimotor polyneuropathy (0.12%), polymyositis (0.12%), acute schizophrenia (0.12%) and other bizarre neurological syndromes (0.36%). Amongst all the complications, the neurological manifestations varied across patients. Occurrence of polyneuropathy conditions such as Guillain Barre Syndrome was also reported as a sequela of typhoid fever [3]. One of the rare neurological manifestations of Typhoid is Auditory Neuropathy Spectrum Disorder (ANSD). It is a unique type of hearing disorder with normal cochlear function and impaired neural conduction, resulting in poor speech perception, even in quiet or in the presence of background noise. The present study is a case report highlighting Auditory Neuropathy Spectrum Disorder as a consequence of Typhoid fever in three cases. The incidence of neurological complications associated with Typhoid ranges between 5%-35% [4]. Apart from the above-mentioned neurologic manifestations, ANSD was noted in three patients associated with typhoid fever, highlighted in this study. This challenging condition persists even when the individual becomes afebrile after treatment. Since there is a dearth of literature regarding the occurrence of ANSD after an attack of Typhoid, the present study was carried out to highlight the probable underlying pathophysiologic mechanisms and audiological findings in these cases.

Aim and Objective of the study

The present study aims to highlight the occurrence of auditory neuropathy spectrum disorder as a sequela of typhoid fever.

Case Presentation

A single case study was carried out in the present study. Three cases were reported at All India Institute of Speech and Hearing, Mysuru, with the complaints of reduced hearing sensitivity in both ears, blocking sensation and poor speech understanding in a group conversation. They all were females having 18 (Case I), 19 (Case II) and 20 (Case III) years of age. All of them belong to families with low socioeconomic backgrounds. The onset of the problem was reported to be gradual after the occurrence of Typhoid within the duration of 1-3 years. The presence of Typhoid was confirmed based on laboratory testing of blood and/or stool culture by certified Physicians. At AIISH, detailed case history was taken, followed by routine audiological evaluation. From case history, it was known that all clients underwent repeated hospital admission due to multiple typhoid attacks. All tests and protocols used for the present study were approved by the AIISH Ethical Committee and  the protocol used in the study complies with recommendations of the Declarations of Helsinki and Tokyo, for humans. Informed consent was taken from all the patients participating in the study. An Otoscopic examination was carried out to rule out the presence of any external or middle ear complication. Middle ear status was assessed by immittance evaluation. Further, clients underwent pure tone audiometry for estimation of hearing sensitivity. Since all the three clients reported problems in speech understanding, speech perception in noise was also carried out along with routine speech audiometry consisting of speech recognition threshold, speech identification score, and uncomfortable loudness level. Otoacoustic emissions were administered to check the status of outer hair cells. Auditory brainstem response for the site of lesion testing was also carried out to rule out the presence of any space-occupying lesion and the neuronal integrity. Late latency responses were also administered to check the cortical response. The audiological profile of all three patients is displayed in Table 1.

Table 1: Audiological profile of all the three patients diagnosed as ANSD.

Note. PTA: Pure Tone Average, SIS: Speech Identification Score, Tym: Tympanometry, Reflex; Acoustic Reflex, OAE: Otoacoustic emissions, CM: cochlear microphonics, ABR: Auditory Brainstem Response, LLR: Late Latency Response, NR: No Response, P: Present, A: Absent R: Right Ear. L: Left Ear, ipsi: Ipsilateral, contra: Contralateral

Otoscopic examination revealed a bilateral normal tympanic membrane with the cone of light present. Immittance evaluation revealed ‘A’ type tympanogram indicating normal middle ear function with absent ipsilateral and contralateral acoustic reflexes in all individuals. An experienced otorhinolaryngologist also confirmed the normal middle ear function. Pure tone audiometry revealed bilateral moderate sensorineural hearing loss (Case I), moderate sensorineural in the right ear and mild sensorineural hearing loss in the left ear (Case II), and Bilateral mild sensorineural hearing loss (Case III). All three cases had a low frequency rising audiometric configuration, a typical auditory neuropathy spectrum disorder feature. Speech identification scores were poor, ranging from 16% to 84%. Further speech perception in noise scores was highly deteriorated, ranging from 0% to 40%. Auditory brainstem responses were absent at 90 dB nHLat a repetition rate of 11.1/sec in all the three individuals tested, shown in Figure 1, 2 and 3. Cochlear microphonics was visualized in one of the cases (Case II), as seen in Figure 2, but the CM was absent in the other two patients (Figure 1 & 3). Outer hair cells functioning were normal in all three cases as revealed by robust transient evoked otoacoustic emissions. LLR were absent in all three cases suggesting affected cortical dys-synchrony. Neurological assessment was carried out by an experienced Neurologist and ruled out the presence of any space-occupying lesion. Based on the audiological profile and neurologist report, all individuals were diagnosed as having primary auditory neuropathy based on the criteria recommended by Starr, Sininger, and Praat [5].

Figure 1:  I Auditory brainstem response recorded in the case I.

Figure 2: Auditory brainstem response recorded in the case II.

Figure 3: Auditory brainstem response recorded in the case III.

In the current study, all affected individuals with Typhoid fever were females indicating that women are more vulnerable to this disease, and underlying pathophysiological mechanisms are affecting even the auditory system as a complication of this disease. Similar findings were reported in the literature [6]. They have studied the occurrence of sensorineural hearing loss after typhoid fever. The authors attributed host susceptibility, endotoxins, arteritis, and ischemia as the possible mechanism causing lesions in the inner ear. Inflammation of the cochlear and the vestibular system secondary to endotoxemia and cytokine-mediated damage is also reported as a possible cause of hearing loss in patients with Typhoid fever [7]. In the current study, we found out that typhoid can affect neural synchrony or neural firing and results of audiological tests concluding auditory neuropathy spectrum disorder. Excessive increase in body temperature, which is mediated by hypothalamic thermo-regulatory control due to this endemic disease, can result in intracranial hypotension, manifested with a variety of symptoms like severe headaches and even coma [8]. Intracranial hypotension would have damage to the normal functioning of the auditory nerve, which could have led to the clinical manifestation of ANSD. Neurological issues due to infection with salmonella Typhi are already reported in literature. Typhoid fever outbreak in Malawi–Mozambique in 2009 reported different associated problems among the affected individuals. 40 out of 303 patients had neurological problems. Among the 40 patients, upper motor neuron signs (e.g. hyperreflexia, ankle clonus, or spasticity) were reported by 17 patients. Other neurological findings included ataxia in 22, early encephalopathy in 15, subjective hearing loss in 9, and parkinsonism in 8 patients [9]. Manifestation of neurological deficits without meningitis among patients with Typhoid fever is assumed to be the result from multiple causes such as Hyperpyrexia, dehydration, electrolyte and acid-base with balance, bacteremia and toxaemia [10, 11]. Acute autonomic neuropathy was also reported in a patient with typhoid fever [12].  Among patients with Typhoid fever, hyperpyrexia or rise in body temperature, more than 430 Celsius, electrolyte disturbances and typhoid neurotoxins are presumed to have led to the permanent disrupted neural firing and neural synchrony, which would have eventually led to ANSD. Tech-chon [13] also reported  patients with typhoid fever manifesting diffuse neuronal damage, nonspecific vascular changes with thrombosis and haemorrhages, and abscess formation in brain.Similar kind of underlying pathophysiological mechanism would have cause neural synchrony resulting in ANSD. Khodari, Baig, Alkhateeb and Naeem [14] reported a  patient with acute sensorineural hearing loss which was caused due to salmonella Typhi, treated with intravenous antibiotics and systemic steroids. They claimed that the hearing loss gradually improved and entirely resolved to normal status within 3 to 4 weeks post-treatment. It was already reported that systemic steroids could be used as the possible treatment to reduce inflammation of the labyrinth, or cochlear nerve result from the inflammation caused by the salmonella Typhi; where similar treatments are used to cover the idiopathic form of acute sensorineural hearing loss [15]. Hence it is highlighted that the hearing status needs to be checked when a patient is infected with Salmonella Typhi. The treatment for the inflammation for the end organ for the hearing and balance system needs to be done, where possible improvement in hearing can be made if the treatment is done within the ‘golden hours’. However, permanent damage of the functioning of the inner ear and even auditory nerve may result if the hearing loss is overlooked at the initial treatment plan, which may be one of the probable causes of hearing loss seen among the three patients with ANSD.

The cases with recurrent Typhoid and associated speech understanding problems need to undergo detailed audiological and neurological investigations. This helps to rule out the existence of any associated neurological condition such as ANSD. Hyperpyrexia (> 430 Celsius), electrolyte disturbances and typhoid neurotoxins would have caused the disrupted neural firing. The study also highlights the importance of the typhoid conjugate vaccine, which was recently added to immunization in India. Though antibiotics can be an effective treatment, controlling the disease is a big problem due to the spread of multi-drug-resistant strains. Preventing the disease by maintaining hygiene, consuming pure water and food, proper vaccination is highly recommended. The need for detailed audiological and neurological assessment to detect any neuropathic condition in individuals who had multiple attacks of Typhoid is also recommended so that an effective treatment plan for the restoration of hearing can be done.

Authors would like to Acknowledge Director, All India institute of speech and Hearing, Mysuru, affiliated to the University of Mysore for allowing us to carry out the study. Authors extend their gratitude to all the participants for their patient cooperation.

Funding Statement

This study has not received funding from any agency.

Conflict of Interest

None

Author Contributions

First Author: Involved in Study design, acquisition of data, Statistical analysis and drafting the manuscript.

Second Author: interpretation of the results, and critical revision of the manuscript.

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