Article, Neurology

Multiple cranial nerve neuropathies, ataxia and, areflexia: Miller Fisher syndrome in a child and review

Unlabelled image American Journal of Emergency Medicine 35 (2017) 661.e1-661.e4

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Case Report

Multiple cranial nerve neuropathies, ataxia and, areflexia: Miller Fisher syndrome in a child and review

Abstract

Ataxia in children mainly occurs from postinfectious cerebellar atax- ia, toxic ingestions, and labrynthitis. An unusual cause is the Miller Fish- er syndrome (MFS) which is considered a variant of Guillain-Barre syndrome. It is a self-limiting demyelinating disease of the Peripheral nervous system characterized by the triad of ophthalmoplegia, cerebel- lar ataxia, and areflexia. We report on MFS in a child with review of the medical literature. The medical literature was searched using MEDLINE/ PubMed, Cochrane Library, and EMBASE. The references from the arti- cles were also reviewed. A 5-year-old girl presented with difficulty walking, diplopia, and dysarthria. Her neurologic examination showed multiple cranial palsies, marked truncal ataxia, and absent deep tendon reflex. Her respiratory status worsened over 2 days, requiring orotracheal intubation. She ultimately was diagnosed with MFS and was treated with intravenous IgG with improvement in her symptoms. MFS is well described in adults and occasionally in children. It is associ- ated with elevated antiganglioside anti-GQ1b IgG antibody. Treatment is supportive with occasional use of intravenous immunoglobulins or plasmapheresis in drug-resistant cases. Prognosis is usually good, but on rare occasions, Respiratory insufficiency may occur, and to recognize its occurrence, frequent assessment of the respiratory status is required.

In children, the most common causes of ataxia include postinfectious cerebellar ataxia, toxic ingestions, and labrynthitis [1]. An unusual cause is the Miller Fisher syndrome (MFS) which is a variant of Guillain-Barre syndrome (GBS). It is an acquired acute nerve, self-limiting demyelinat- ing disease of peripheral nervous system characterized by the triad of internal and external ophthalmoplegia, cerebellar ataxia, and areflexia [2]. This syndrome has been well described in adults, with only occa- sional case reports in children. A child is presented who was diagnosed with MFS with a progressive form of this disease requiring intubation for respiratory failure.

A 5-year-old girl presented to the emergency department (ED) with a 2-week history of difficulty walking, diplopia, and dysarthria. She de- nied fever, nausea, vomiting, diarrhea, or abdominal pain. She was hos- pitalized at another hospital. She had a normal computed tomographic scan of the head, magnetic resonance imaging (MRI) of the head, cere- brospinal fluid (CSF) analysis and culture, and electroencephalogram. She was discharged with no etiology to her clinical symptoms.

Her symptoms worsened, and she arrived in our ED because her mother had concerns for possible stroke. Her medical history includED asthma, anemia, frequent Otitis media, and bilateral myringotomy tube placement. Her medications included albuterol, topical nystatin for oral candidiasis, and multivitamins with iron for mild Iron deficiency anemia. She was recently treated for 2 weeks with high-dose amoxicillin

for otitis media that was thought to be the proximal cause of her oral can- didiasis. She had no allergies, and her mother had history of migraines. Her immunizations were current, with her last immunization at the age of 15 months, which included measles, mumps, rubella; Heamophilus influenzae type b conjugate; pneumococcal conjugate; inactivated polio- virus; and diphtheria, tetanus toxoid, and acellular pertussis.

Her temperature was 37.8?C, heart rate was 88/min, and respiratory rate was 20/min with a room air pulse oximetry of 99%. On examination, she was in no acute distress. Her oral mucosa revealed oral candidiasis. She had no lymphadenopathy. Results of her lung and heart examina- tion were normal. She had no hepatosplenomegaly. Her neurologic ex- amination showed a dysconjugate gaze with right-sided nystagmus. She had cranial nerve III, IV, V, VI, X, and XI palsy. Results of her motor and sensory examinations were normal. Her cerebellar examination re- vealed a wide base gait with marked truncal ataxia and dysmetria. Her deep tendon reflexes of the lower extremities were absent, with 1⁺ in the upper extremities.

Her complete blood count showed a white blood cell count of 9500/ mm³ with 77% neutrophils. Her hemoglobin was 10.6 g/dL (normal for age and sex, 10.9-13.3 g/dL) and platelets were 195 000/mm³. Her elec- trolytes were normal. Repeat CSF analysis showed an elevated protein of 120 mg/dL (normal, 12-60 mg/dL), normal glucose, and 1 white blood cell per cubic millimeter.

She was hospitalized, and her respiratory status worsened, requiring orotracheal intubation on the second day. Bacterial and viral CSF cul- tures were negative. Other negative studies included CSF Lyme poly- merase chain reaction, serum Epstein-Barr virus titers, HIV enzyme- linked immunosorbent assay antibody, antinuclear antibody test, serum angiotensin-converting enzyme, acetylcholinesterase antibody, respiratory syncytial virus antigen, and influenza A and B antigens. Her serum levels of immunoglobulin IgG anti-CQ1b antibody were ele- vated. Her hospital course was complicated in that she was not able to be weaned off the ventilator and required a tracheostomy. Result of re- peat head MRI of the head was normal. She was given intravenous im- munoglobulin 2 g/kg, and her symptoms slowly responded over the next few weeks. She was discharged to the children’s rehabilitation hos- pital and recovered well.

Approximately 5% of patients with GBS have an unusual variant of the disease called the Miller Fisher syndrome. Ophthalmoplegia and atax- ia have both long been known to occur separately as prominent signs in patients with GBS [3-5]. In 1932, Collier [3] first described patients who developed 4-limb peripheral neuritis associated with bilateral ophthalmoplegia of rapid onset and recovery, but failed to describe any associated ataxia and areflexia. MFS was first described in 1956 by Charles Miller Fisher who first reported 3 adult patients with total exter- nal ophthalmoplegia, severe ataxia, and loss of the tendon reflexes and

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viewed the symptoms as a separate disease, an unusual variant of acute id- iopathic polyneuritis [2]. MFS is well described in adults in the third to sev- enth decade; it is less common in children and rare in infants [6-10]. MFS is characterized by the triad of internal and external ophthalmoplegia, cere- bellar ataxia, and areflexia in the absence of limb and truncal weakness.

The classic pathologic mechanism of MFS is peripheral nerve demy-

elination. Gangliosides are molecules composed of glycosphingolipids (ceramide and oligosaccharide) that are concentrated in the nervous system. MFS is associated with elevated antiganglioside IgG anti-GQ1b antibody [10-16]. GQ1b is a tetrasyaloganglioside that is enriched in the Cranial nerves that control the extraocular muscles. This antibody is present in 85% to more than 90% of patients with MFS but is not spe- cific to MFS, which is why some patients may develop GBS or one of its other variants, such as Bickerstaff brain stem encephalitis [17-19]. These antibodies have been implicated in causing the ophthalmoplegia associ- ated with MFS. Historically, approximately two-thirds of patients with GBS have an infection preceding the onset of symptoms, and half have been shown to have Campylobacter jejuni, whereas others have Hae- mophilus influenzae[20-22]. It is known that lipopolysaccharides from some strains of C jejuni mimic the structure of human gangliosides, and attention has focused on the possibility that molecular mimicry is a factor in the pathogenesis of human neurological disease [23-26]. Pa- tients with MFS have an immunologic cross-reactivity between the lipo- polysaccharide of C jejuni and ganglioside GQ1b [6,27]. Other evidence of an antecedent infection as the impetus for an immune response against host nerve gangliosides includes serological isolation of infec- tious agents during the acute phase of the disease, such as Coxiella burnetti, Mycoplasma pneumoniae, Streptococcus pyogenes, Staphylococ- cus aureus, Escherichia coli, Pasteurella molticida, Epstein-Barr virus, cy- tomegalovirus, Varicella-zoster virus, mumps virus, influenza A, and HIV [28-34]. It has been also associated in adults with chronic lympho- cytic leukemia, Hodgkin lymphoma, Burkitt lymphoma, Lung cancer, systemic lupus erythematosus, and rheumatoid arthritis [35-39]. Al- though postvaccination GBS has been reported, there have only been 4 previously reported cases of postvaccination MFS [40,41].

The evaluation in the ED rests mainly on a Detailed history and ex- tended Neurological examination. Physical examination initially should focus on identifying life-threatening conditions that may require imme- diate intervention. Presence of confusion, hallucinations, mood distur- bances, or somnolence must be excluded. Such symptoms may occur from toxic ingestions, demyelinating diseases such as acute disseminat- ed encephalomyelitis , stroke, or meningoencephalitis. The presence of papilledema, pupillary dilation, and lateral rectus palsy indicates elevat- ed intracranial pressure. Motor examination should focus on eliciting weakness in an anatomically significant pattern, such as one-half of the body or both lower extremities. Often, a younger child with hemiparesis or paraparesis will present with ataxia as opposed to focal weakness of the affected body part (ie, “paretic ataxia”). A detailed cerebellar examination should be performed. Dysfunction of midline cerebellar structures causes truncal ataxia and head tremor. Disorders of the lateral aspects of the cerebellum cause limb ataxia, which can be evaluated by the finger-nose or finger-finger test, intention tremor, and dysdiadochokinesia. In the lower extremity, one can perform the heel-shin test to look for incoordination. Cerebellar incoordination tends to be most prominent when movements are performed slowly. Ataxia from pathology of the cerebellum is not exacerbated by eye clo- sure; therefore, a Romberg test result will be negative. Presence of nys- tagmus may arise from pathology in the vestibular system (“peripheral” type) or the central nervous system (“central”). Certain specific types of nystagmus, such as opsoclonus, may rarely be seen. Finally, a compre- hensive sensory examination and an examination of deep tendon re- flexes should be performed to rule out diseases of peripheral nerves or roots (ie, “sensory” ataxia). Plantar responses are not affected by dis- eases of the cerebellum; hence, a positive Babinski test result is indica- tive of disease processes in the upper motor neuron pathway, outside of the cerebellum.

There are no tests to absolutely confirm this syndrome, hence limit- ing the diagnosis to a clinical one based on the presence of the clinical triad of ataxia, ophthalmoplegia, and universal areflexia, along with clinically insignificant limb weakness [1,2]. It is important to recognize this syndrome so that treatment can be instituted promptly. In a review of 223 patients with MFS by Berlit and Rakicky [42], a viral infection pre- ceded the neurological symptoms in 71.8%. Symptoms are usually acute in onset and usually occur 10 days (72 hours to up to 2 weeks) after pre- ceding infection [42,43]. Diplopia is usually the first symptom in chil- dren old enough to complain about it [17]. The classic cranial nerve abnormality is ophthalmoplegia; however, other cranial nerves may be involved in greater than 50%, including cranial nerves VII, IX, X, and XII [42]. Ophthalmoplegia is usually initiated by a limitation in abduc- tion [44]. The external ophthalmoplegia can be unilateral or bilateral and complete or incomplete. Optokinetic nystagmus and Bell phenom- enon (palpebral oculogyric reflex) are usually lost. However, nystagmus may be present in some children as in this case [45]. Ptosis is generally present in most patients. Other associated features may include pupillary abnormalities and blepharoptosis [46]. The ataxia is the most disabling clinical feature of MFS. Although there is moderate limb ataxia, the truncal ataxia is generally more severe. Areflexia occurs in 80% of patients [42].

Other symptoms seen in MFS include dysphagia, dysphonia, facial paralysis, tetraparesis, or respiratory insufficiency [42]. Respiratory dif- ficulties are more frequent in elderly patients and are rare in children, and they usually require mechanical respiratory support; therefore, Close monitoring of respiratory status in a pediatric intensive care unit (PICU) is recommended [31]. In adults, titubation and descending tetraparesis increased the need for intubation from respiratory failure [47]. Recurrences of MFS have only rarely been reported [42,48].

Whereas one of the complications of GBS is progression to respirato- ry failure, MFS usually has a benign course. Progressive respiratory mus- cle weakness leads to respiratory insufficiency [49,50]. In addition, most patients requiring intubation probably have some form of GBS with ophthalmoplegia. Bedside pulmonary function tests (PFTs), such as a forced vital capacity b20 mL/kg and a negative inspiratory force (NIF) b30 cm H₂O, may be useful in predicting potential impending re- spiratory failure and serve as a baseline for serial measurements. NIF is the greatest negative pressure the patient can generate [51]. It is mea- sured by asking patients to inhale as hard as they can with measure- ment of the negative pressure that they generate using a pressure gauge. It is a measurement of the strength of the inspiratory muscles, primarily the diaphragm. FVC is the largest volume of gas that a patient can exhale. Patients are asked to take a full breath in and then exhale maximally, with measurement of the exhaled volume. FVC reflects a global measurement of the patient’s ventilatory ability, which takes into account inspiratory and expiratory muscle strength as well as pul- monary compliance. FVC is arguably the best single test of ventilatory capability because it integrates inspiratory and expiratory muscle strength as well as pulmonary compliance [52]. However, poor PFT re- sults correlate with risk of respiratory failure but are not highly specific for predicting intubation. As with any critically ill patient, the decision to intubate should be based primarily on clinical assessment at the bed- side. Important elements include Work of breathing, respiratory rate, oxygenation variables, and trends in these values. Check for retractions of the supraclavicular fossa and intercostal spaces as indicators of respi- ratory accessory muscle usage. Use of these muscles in MFS patients is an important sign that respiratory effort may not be sustained. Other in- dications for intubation would include bulbar dysfunction with an in- ability to handle secretions and protect the airway. Significant hypoxemia would suggest either ongoing aspiration or atelectasis, ei- ther of which would be very concerning. The overall tempo of the illness and Clinical context, including trends in pulmonary function, provides some additional information. Because PFTs are poorly specific for predicting respiratory failure, preemptive intubation based solely on PFTs may lead to unnecessary intubations and iatrogenic harm. A safer approach to patients with poor pulmonary function who do not

A.E. Muniz / American Journal of Emergency Medicine 35 (2017) 661.e1-661.e4 661.e3

clinically require intubation is close PICU-level observation with intuba- tion only if clinically indicated. It is also possible that noninvasive venti- lation, bilevel positive airway pressure, is an alternative to intubation in patients without hypercapnia who are able to clear secretions. The use of Neuromuscular blockers for intubation may impair neuromuscular function and delay extubation. The initial ventilator mode is typically “assist control/volume control.”

The differential diagnosis in a child with ataxia includes acute

postinfectious cerebellar ataxia, toxic ingestions, Arnold-Chiari malforma- tion, Dandy-Walker syndrome, Friedrich ataxia, Joubert syndrome, labrynthitis, benign paroxysmal vertigo, cerebellar stroke, acute dissemi- nated encephalomyelitis , meningoencephalitis, rhombencephalosynapsis, opsoclonus-myoclonus syndrome, basilar migraine, cerebellar hemor- rhage, pseudotumor cerebri, Leigh syndrome, traumatic vertebral dissec- tion, concussion, head trauma, Multiple sclerosis, Heat stroke, botulism, tick paralysis, toxic ingestions (anticonvulsants, lead, eucalyptus oil, insec- ticides, benzodiazepines, dextromethorphan, antineoplastics [fluorouracil, cytarabine, methotrexate], toluene, cocaine, heroin, phencyclidine, alcohol, marijuana and methadone), and shellfish poisoning [1,53-58]. When the ataxia is accompanied by ophthalmoplegia, the differential may include myasthenia gravis, multiple sclerosis, Lyme disease, diphtheria, Wernicke encephalopathy, brain stem neoplasms, neuroblastoma, medulloblastoma, acute cerebrelitis, and brain stem encephalitis, such as in cases of neurosyphilis, acute poliomyelitis, and Herpes encephalitis [1,23,59,60].

The laboratory diagnosis of MFS is highly suggested with elevated antiganglioside anti-CQ1b antibodies in blood serum analyzed by enzyme-linked immunosorbent assay, but approximately 10% are nega- tive for this antibody [13,14,61]. Serum antignglioside antibody titers are at their peak at clinical presentation, and they usually become nega- tive within 3 to 4 weeks, concomitant with clinical recovery. Cerebrospi- nal analysis may show increased proteins in the absence of pleocytosis (or albuminocytogenic dissociation) but is helpful in excluding other viral eti- ologies causing encephalitis [1,42]. The albuminocytologic dissociation may not occur until weeks after the symptoms; thus, its absence does not exclude the diagnosis. However, it is only present in about 65% of those with MFS.

The results of electrophysiologic studies on patients with MFS have been contradictory. Some studies revealed no peripheral nerve abnor- malities [62]. Most studies, however, show peripheral nerve involve- ment such as abnormalities in distal motor latencies, motor conduction velocities, sensory conduction velocities, F-wave latency, and H-reflexes [43,63,64]. Electroencephalogram may show slow exces- sive slow-wave activity or can have a normal result [8]. Result of a com- puted tomographic scan of the head is normal but may exclude other causes of ataxia, such as a tumor or hemorrhage. Result of MRI of the head is also usually normal but may be indicated if multiple sclerosis is considered in the diagnosis. Recently, enhancement of cranial nerves (abducens and facial) was demonstrated in children with MFS syn- drome by double-dose gadolinium MRI [65,66].

Virtually all patients with suspected MFS should be hospitalized to a monitored bed with frequent observation of respiratory parameters. All should also have a neurologic consultation. Most patients with MFS im- prove completely by 8 to 12 weeks without treatment. Patients requir- ing PICU admission include those with orthopnea, dyspnea at rest, increased work of breathing (retractions), weak cough, prominent neck flexion weakness, difficulty in clearing secretions, rapid shallow breathing, paradoxical abdominal breathing, baseline FVC b30 mL/kg and NIF b40 cm H₂O, or broken speech in need of pause and breath after every few words [31,47,49].

The effect of immunomodulatory treatment such as immunoglobu- lin or plasmapharesis in drug-resistant cases is a controversial issue in MFS because only anecdotal evidence of benefit exists [67-69]. Immunoadsorption of the anti-CQ1b from the serum of patients with MFS has been accomplished with marked decreased in their serum anti-GC1b titers and improvement in their ataxia and ophthalmoplegia [59]. In a retrospective case series in adults, neither intravenous

immunoglobulin nor plasmapheresis influenced patient outcomes, pre- sumably because of the good nature recovery [67]. In addition, there are no randomized or nonrandomized prospective controlled trials of im- munotherapy in MFS [70]. Because MFS is a self-limiting disease and re- covery is spontaneous, a case-control study is needed to evaluate the effects of immunotherapy treatment. The use of corticosteroids also has not been shown to be beneficial [71]. Patients with MFS usually have a good prognosis and no residual deficits. resolution of symptoms is generally complete by 6 months [46].

Ataxia in children most commonly occurs from acute postinfectious cerebellar ataxia, toxic ingestions, and labrynthitis [1]. On occasion, the MFS may be the cause of the ataxia. It is suspected in a child with the triad of ophthalmoplegia, cerebellar ataxia, and areflexia. Treatment is supportive and may include plasmapheresis and administration of in- travenous immunoglobulins. Prognosis is usually good, but on rare oc- casions, respiratory insufficiency may occur, and to recognize its occurrence, frequent assessment of the respiratory status should be per- formed in a monitored setting.

Antonio E. Muniz, MD

827 Via Del Sur, Mesquite, TX 77401 E-mail address: [email protected]

http://dx.doi.org/10.1016/j.ajem.2016.07.042

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Multiple cranial nerve neuropathies, ataxia and, areflexia: Miller Fisher syndrome in a child and review

Madhavan S. Geetha, Bhargavan PV. recurrent MIller Fisher syndrome. J Assoc Phy- sicians India 2004;52:582-4.

Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and Radiological features of acute disseminated encephalomyelitis in childhood. Neurology 2001;56(10):1308-12.

Thakkar K, Maricich SM, Alper G. Acute ataxia in childhood: 11-year experience at a major pediatric neurology referral center. J Child Neurol 2016;31(9):1156-6110.

Leave a Reply Cancel reply

Thakkar K, Maricich SM, Alper G. Acute ataxia in childhood: 1 1-year experience at a major pediatric neurology referral center. J Child Neurol 2016;31(9):1156-6110.