Pediatric Miller Fisher syndrome mimicking anti-histaminic drug toxicity

Gowsinivedha Natarajan; Vikneswari Karthiga Serane; Podhini Jegadeesan; Soundararajan Palanisamy

doi:10.4103/ipcares.ipcares_171_22

CASE REPORT

Year : 2023 | Volume : 3 | Issue : 1 | Page : 43-46

Pediatric Miller Fisher syndrome mimicking anti-histaminic drug toxicity

Gowsinivedha Natarajan, Vikneswari Karthiga Serane, Podhini Jegadeesan, Soundararajan Palanisamy
Department of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth University, Puducherry, India

Date of Submission	11-Jul-2022
Date of Decision	23-Jan-2023
Date of Acceptance	24-Jan-2023
Date of Web Publication	27-Feb-2023

Correspondence Address:
Dr. Vikneswari Karthiga Serane
Department of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth University, Pillayarkuppam, Puducherry - 607 402
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_171_22

Abstract

Background: Miller Fisher syndrome (MFS) is a rare condition in childhood, characterized by acute-onset ataxia, ophthalmoplegia, and areflexia. It is mostly preceded by viral and bacterial infections, and the pathogenesis is speculated to be an immune response to cross-reacting antigens. We describe a case of acute ataxia which was initially misdiagnosed as antihistaminic toxicity and later emerged to be MFS. Clinical Description: A 4.5-year-old girl presented with acute-onset ataxia, giddiness, and limb pain, following toxic ingestion of an antihistaminic drug (chlorpheniramine) that had been prescribed for an upper respiratory infection. The absence of waning symptoms, new manifestations, and undetectable drug levels prompted us to consider an alternate diagnosis. Management: Magnetic resonance imaging of the cranium and spine was unremarkable. Hence, a central nervous system infection was considered. Cerebrospinal fluid (CSF) analysis revealed albumin-cytologic dissociation, a negative viral panel, and sterile culture. Serum anti-GQ1b antibody of immunoglobulin G type was positive. A nerve conduction study revealed absent H-reflexes in both gastrocnemius muscles. A diagnosis of MFS was made based on clinical features, CSF albumin-cytologic dissociation, positive anti-GQ 1b antibody, and absent H reflexes. She was treated with intravenous immunoglobulin therapy, following which there was an improvement in 1 week and complete recovery within 3 months. Conclusion: Although a rare entity, we need to consider MFS in the differential diagnosis of ataxia when the neurological signs persist beyond the expected time duration so that investigations can be planned accordingly and timely immunotherapy initiated.

Keywords: Child, GQ1b ganglioside, Miller Fisher syndrome

How to cite this article:
Natarajan G, Serane VK, Jegadeesan P, Palanisamy S. Pediatric Miller Fisher syndrome mimicking anti-histaminic drug toxicity. Indian Pediatr Case Rep 2023;3:43-6

How to cite this URL:
Natarajan G, Serane VK, Jegadeesan P, Palanisamy S. Pediatric Miller Fisher syndrome mimicking anti-histaminic drug toxicity. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Mar 22];3:43-6. Available from: http://www.ipcares.org/text.asp?2023/3/1/43/370525

Accidental poisoning due to the ingestion of sweetened syrups is a common household hazard in children. Drug intoxication is a common cause of ataxia. Most over-the-counter medications prescribed for cough and cold contain antihistaminic drugs. These are known to cause neurotoxicities such as drowsiness, seizures, visual disturbances, and coma. It also results in an anticholinergic toxidrome characterized by anhidrosis, fever, flushing, delirium, and mydriasis.^[1]

Miller Fisher syndrome (MFS) is a clinical variant of Guillain–Barre syndrome (GBS), a peripheral demyelinating disorder. It was first described in 1956 in patients presenting with the clinical triad of ataxia, ophthalmoplegia, and areflexia.^[2] Since then, several cases of MFS were reported, with varied spectra of presentations. MFS is a rare condition with an annual incidence of about 1 affected individual per million population.^[3]

We report a child initially diagnosed as a case of acute ataxia secondary to antihistaminic drug toxicity. Later, the development of additional characteristic clinical manifestations in the setting of undetectable drug levels prompted us to consider the possibility of MFS. The purpose of presenting this case is to highlight the fact that in some instances, clinical appearances may be deceptive, and if the natural course of illness does not manifest, despite concrete evidence of a plausible cause, additional causes should be actively sought. Informed written consent has been obtained from the child's parents for publishing the case details and her clinical picture.

Clinical Description

A 4 ½-year-old girl was brought by her parents with acute onset of history of excessive drowsiness, unsteady gait, frequent falls, and restricted eye movements for 5 days. The night before the onset of symptoms, she had inadvertently drunk an entire bottle (60 ml) of an antihistaminic syrup (chlorpheniramine maleate). This had been prescribed for fever, cough, and coryza ascribed to an upper respiratory tract infection which she had for a week. The syrups concentration was 4 mg/5 ml, according to which she had ingested 48 mg of the drug, a toxic dose of 4 mg/kg/dose. The next day morning she exhibited excessive drowsiness and difficulty in walking. Her parents also observed that she was unable to move both her eyes in all directions, resulting in her only looking straight. There was no history of blurred or double vision. She was immediately taken to a local practitioner who reassured them and sent her home. She was brought to us 5 days after ingestion when these symptoms failed to resolve. In addition, she also complained of giddiness since she had ingested the cough syrup. She had also developed concurrent pain in both lower limbs. This resulted in her not being able to get up by herself from bed, unsteadiness while walking, a tendency to fall, and the requirement of support while walking. She was able to use both upper limbs and turn in bed by herself. There was no history of delirium, irritability, hallucinations, speech abnormality, facial asymmetry, hearing difficulty, dysphagia, the nasal twang in voice, feeding difficulty, headache, vomiting, or involuntary movements. She did not have bowel or bladder incontinence. There were no autonomic disturbances such as sweating, palpitation, hypertension, or flushing. Cholinergic symptoms such as urinary retention, anhidrosis, flushing, blurring of vision, or delirium were observed. There was no history of fever with rash, loose stools, joint pains, trauma to the spine, vaccination, or any other intramuscular injection in the recent past. There was no similar history or hospitalization in the past. The child had a smooth perinatal period was developmentally normal, and was immunized for age. The family history was not contributory.

On examination, the child was drowsy but was oriented to time, place, and person. The vitals were stable, temperature 98°F, heart rate 90/min, respiratory rate 24/min with no retractions, and blood pressure 96/72 mm Hg. Her weight was 14 kg, height 102 cm, and body mass index was normal for her age. There were no neurocutaneous markers or hyperpigmented skin lesions. Her skull and spine were normal. The Glasgow Coma Scale score was 12/15 (best motor-6, best verbal-5, and best eye opening-1). There was bilateral ptosis [Figure 1], and complete external ophthalmoplegia with bilaterally fixed mid-dilated pupils. The visual acuity was normal for age, and there were no visual field defects. There was no other cranial nerve involvement. She had a wide-based ataxic gait. Muscle strength was intact in all four extremities. She had generalized hypotonia with hyporeflexia (diminished deep tendon reflexes in all four limbs) and bilateral flexor plantar response. Truncal and limb ataxia was noted. She could not perform the finger–nose test, heel-to-shin test, or tandem walking. Pain and light touch sensation were intact. Meningeal signs were negative. Other systemic examination was unremarkable.

Figure 1: (a) Miller Fisher syndrome-child with bilateral ptosis at the time of initial presentation. (b) Child with Miller Fisher syndrome after 3 months of treatment with IvIg. IvIg: Intravenous immunoglobulin

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Management and outcome

Thus, the child had acute-onset ataxia, giddiness, and ophthalmoplegia. The possible diagnoses considered were drug-induced ataxia, postvaricella cerebellitis, viral encephalitis, and demyelinating disorders (i.e. GBS and multiple sclerosis). Postinfectious cerebellitis due to varicella was ruled out as there was no history of suggestive skin lesions in the recent past. The absence of fever, seizures, and altered sensorium excluded encephalitis. Thus, in view of the onset of symptoms within 7 h of ingestion of the antihistaminic drug, we made the diagnosis of chlorpheniramine maleate poisoning. However, this did not account for ophthalmoplegia. Subsequently, blood and urine samples were sent for drug levels on the day of admission. Furthermore, a complete blood count, serum biochemistry for liver and renal function, and urine routine were done (to rule out complications of drug toxicity) and were within normal limits [Table 1]. Electrocardiogram for detecting arrhythmias associated with antihistaminic drug toxicity was normal. Drug toxicity was ruled out as the cause for the child's manifestations since the levels were undetectable.

Table 1: Laboratory investigations of the child with Miller Fisher'syndrome

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Therefore, we reconsidered the possibility of acute encephalitis and performed a lumbar puncture on the 2^nd day. The cerebrospinal fluid (CSF) analysis showed an increased cell count (10 lymphocytes/mm³) with elevated protein (63 mg/dL), normal glucose (72 mg/dL), and a negative Gram's stain. CSF viral panel for herpes simplex virus, Japanese encephalitis, Cytomegalovirus, and Enterovirus was negative. Blood, urine, and CSF cultures yielded negative results. Magnetic resonance imaging of the brain and spine were normal.

Since the CSF analysis revealed albumin-cytological dissociation, with normal glucose, and clinically, there were no biomarkers toward a central nervous system (CNS) infection, we now considered the possibility of MFS. A nerve conduction study revealed absent H-reflexes in both gastrocnemius muscles. Serum immunoblot assay for gangliosides was positive for anti-GQ1b immunoglobulin G antibodies (level 29). All other ganglioside antibodies (GM1, GM2, GM3, GD1a, GD1b, and GT1b) were negative. In view of the acute CNS symptoms and setting of the pandemic, we considered MFS secondary to COVID-19 infection. However, the nasopharyngeal COVID reverse transcriptase–polymerase chain reaction and serum COVID-19 antibody testing were negative. Thus, a final diagnosis of MFS was made based on the clinical triad of ataxia, ophthalmoplegia with hyporeflexia with a preceding respiratory infection, absent H-reflex, and positive anti-GQ 1b antibody.

The patient was treated with intravenous (IV) immunoglobulin (1 g/kg/day) infusion over 12 h, for 3 days (total dose of 2 g/kg). By the 3^rd day, there was a mild decrease in the giddiness and ataxia, though ocular signs persisted. By day 7 of treatment, her ptosis had improved on the right side, and she was able to walk independently without falling. 2 weeks later, she was able to walk up and down stairs, perform the finger-to-nose test and heel-to-shin test, and demonstrate rapid alternating movements of hands, but could not perform tandem gait. The child was discharged 14 days after treatment. On her follow-up, at her 1-month visit, ptosis was persisting albeit lesser, tandem gait was performed, and both knee jerks were elicited and found normal (brisk). By 3 months, there was a complete resolution of ocular features.

Discussion

The etiopathogenesis of MFS has been postulated to be due to autoimmunity, similar to GBS. Clinical features are usually preceded by symptoms of an infection, as was seen in this case. The common microorganisms implicated are Campylobacter jejuni, Hemophilus influenzae, Cytomegalovirus, Mycoplasma pneumonia, and Enterovirus.^{[4],[5],[6],[7]} Recently, coronavirus has also been associated with pediatric MFS.^[6],[8] Molecular mimicry has been demonstrated for bacteria, but not with viruses. Hence, other possible causes such as the direct neuropathogenic effect of the virus and a dysregulated immune response have also been postulated.^[5],[6],[9]

The GQ1b ganglioside mimicking lipooligosaccharides on Campylobacter jejuni has been linked to MFS.^[5] Immunoglobin G antibodies against GQ1b have become a crucial test done in MFS, with a specificity of 95%.^[10] Although the clinical presentation of MFS in children is similar to adult patients, a lower positivity rate for anti-GQ1b antibodies has been reported in children (22.2%) compared to adults (71.4%).^[11] However, in this particular study, the authors have stated that in most of the pediatric cases testing was delayed, which could be attributed to the discrepancy since antibodies wane with time from the onset of illness. The fact that positive anti-GQ1b antibodies were found in our patient clinched the diagnosis. We did the test in the relatively early phase of the illness.

The incidence of pediatric MFS is lower compared to adults, and a complicated course of the illness has been reported [Table 2]. There have been reports of children needing intubation^{[12],[13],[14],[15],[16]} and a child with central involvement.^[14] Children need close monitoring for the progression of symptoms. Management is in line with GBS and includes intravenous immunoglobulin therapy, with or without plasmapheresis/steroids, and supportive measures, which is similar to the management of MFS in adults. Children had a significantly early recovery (by 1 month) as compared to adults with MFS, as found in a retrospective comparative study.^[11] MFS in children has a benign course with a median recovery time of 1 to 3 months.^[11]

Table 2: Clinical details of published case reports of pediatric Miller Fisher's syndrome

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To conclude, as clinicians, we practice the strategy of looking for the most common and plausible cause that can scientifically explain the clinical manifestations in a patient. However, one must consider alternative diagnoses if the natural course of illness does not conform to the usual pattern, or is unusually prolonged.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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