Clinical characteristics of Guillain-Barré syndrome in children
INTRODUCTION
Guillain-Barré syndrome (GBS) is an acute immune-mediated polyneuropathy, constituting one of the most common causes of flaccid paralysis in children [1]. It is one of the major pediatric emergencies encountered in intensive therapy [1, 2]. The overall incidence of GBS varies by country, being reported as 1 – 2 cases [1, 3] to 100000 population per year, or in average 1.4/100000 per year [4]. In EU countries there are under 7000 cases per year and under 100000 cases around the world. In children GBS is more common between the ages 1 and 5 years [1]. Inflammatory and immune processes caused by the activated immune response of T and B cells by certain infectious agents, are the basis of this demyelinating process, determined by autoimmune disorder. Typically, this condition occurs after an earlier infection caused by certain infectious agents such as Campylobacter Jejuni, Cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, Herpes virus, etc. [1, 5, 6]. Were also described some other causes that could trigger GBS, including immunization, surgical intervention, trauma and bone marrow transplantation [1, 6]. As a result of various causes, antibodies are produced, causing various cross-reactions with myelin gangliosides and other components of nerve fibers of the peripheral nerves, including myelin or axons. Autoantibodies to gangliosides are formed directed against own tissues. Consequently, it destroys the myelin, and blocks the mechanisms of the conductance of the nervous impulse, and the flaccid paralysis develops. Were described several clinical forms of GBS, which are in direct relation to the affected nerve cells [1, 7]. Usually, clinical symptoms of the disease occur within 7 – 14 days after an early infection [7]. GBS in children is associated with a higher incidence of cranial nerve paralysis, developing a more serious form of disease than in adults. In addition, in 40% of children the disease can be associated with the paralysis of the respiratory muscles and in 20% with disautonomia, a symptom similar to that in adults, which aggravates the outcome [8, 9]. In one study it is noted that the clinical characteristics of GBS in different countries could be distinct due to geographical diversity and racial differences [8]. In view of these results, we considered it necessary to carry out a retrospective study in RM, by analyzing the clinical characteristics of pediatric patients with GBS.
AIM OF THE STUDY
Investigation of clinical paraclinical features in children with GBS admitted in the Department of Neurology of the Institute of Mother and Child, Chisinau, Republic of Moldova.
MATERIALS AND METHODS
Were revised medical records of patients admitted in the Department of Neurology of the Institute of Mother and Child, Chisinau, Republic of Moldova, during January 2009 – December 2018. Clinical symptoms were analyzed in 30 children, from which 18 were boys and 12 were girls, who met the inclusion criteria for the GBS diagnosis. Inclusion criteria were as follows: Less than 3 weeks between the onset of symptoms and the inclusion time, the age from 1 to 15 years. Patients were distributed according to age: from 1 to 3 years 11 children (36.7%), from 4 to 5 years 10 children (33.4%), from 6 to 15 years 9 Children (30%). Clinical symptoms were used as a basis of GBS, i. e., rapid progression of weaknesses or paralysis in the limbs, progressive loss of tendon reflexes (TR), electrophysiologic examination, i. e., electromyography (EMG) positive for neuropathy, i. e., decrease or blocking of conductance speed on the nerve, or low responses of wave F. The predominant clinical symptoms were studied, negative, i. e., neuropathic paint, taking into account the time, type and localization of pain, numbness, tingling or stinging, muscle cramps, etc., as well as positive, i. e., weaknesses in limbs, awkward walking and instability. Among the group of children with pain were 11 children between 1 and 3 years, at which this symptom manifested by agitation, screams, continuous crying and restless sleep. The symptom of pain was also found in 9 of 10 children of 4 – 5 years and in 6 out of 9 older children. The history of infections, immunization or interventions, as well as the first manifestations of the disease was important to precise the diagnosis. All patients were exposed to clinical and paraclinical testing using neurological, biochemical, bacteriological, virological and immunological testing as well as lumbar puncture with CSF exam, neurophysiological exam (EMG) and optional imaging, i. e., cerebral or spinal MRI. For the evaluation of muscle weakness, the MRC scale has been used, scoring from 5 to 0 points: (5) points – normal power, (5-) points – barely noticeable weakness, (4+) points – overcoming strong resistance, (4) – overcoming moderate resistance, (4-) – overcoming weak resistance, (3) – overcoming gravity, (2) – movement only when gravity is eliminated, (1) – tremor or weak contraction and (0) points – lack of contractions, which helped to assess the force of the muscles groups, e. g., mimic muscles, flexors and extensors of the neck, and upper and lower limbs. The tendon reflexes were evaluated according to the National Institute of Neurological Disorders and Stroke (NINDS) scale, as follows: “0“ points – absent reflex response, “1“ – diminished reflexes compared to normal, usually presents only after distraction, “2“ – reflexes less than that normal, “3“ – brisk, (4) – very brisk includes clonuses. Superficial and deep sensitivity was examined according to the traditional techniques existing in neurology only in children older than 5 years of age. The CSF exam, which in the case of GBS would indicate increasing of proteins and cells after the first week of onset of clinical symptoms, was not suggestive in all cases. Electrophysiological research was carried out using detection of stimuli, completed with the evoked motor potential and electromyographic examination. The data about medical treatment for GBS was obtained from the medical records of patients enrolled in the study. We analyzed the type and effectiveness of the treatment administered. Patient data were introduced in a study protocol, with the following content: passport data, personal history and history of previous illness, history of the present disease, somatic and neurologic status, results of muscle strength assessment using Medical Scale Research Council/MRC scale and the data of laboratory examinations performed, as well as electrophysiological and imaging data. Exclusion criteria were status of coma with communication disorders, other CNS infections, diseases of liver and renal insufficiency.
RESULTS
Most children (27) have a history of previous disease 1 – 3 weeks before the onset of neurological condition, namely, in 14 cases (46,7%) acute respiratory infection, in 10 cases (33,3%) gastrointestinal disorders, including abdominal pain or diarrhea, in 3 cases (10%) unexplained febrile status, in 2 cases (6,7%) immunization, in one case (3,3%) trauma. Thus, 24 children (80%) have had postinfectious onset preceded with respiratory (46,7%) or gastro-intestinal symptoms (33,3%). In investigated patients were confirming the following infections, namely, cytomegalovirus in 5 cases (16,7%), EpsteinBarr virus in 6 cases (20%), herpes simplex virus in 3 cases (10%), Mycoplasma penumoniae in 3 cases (10%), varicella-zoster virus in 2 cases (6,7%), Campylobacter jejuni in 7 cases (23,3%), and in 4 cases (13,3%) infections were not detected. One of the most common symptoms which preceded other neurological signs was pain. Of the 30 children with GBS, 26 (86.7%) presented with pain prior to neuropathy. In 4 cases (15.4%) the pain manifested 3 days until the onset of other symptoms of the disease, in 8 cases (30.8%) – 2 days before, in 9 cases (34.6%) – the day before, in the other 5 cases (19.2%) with other symptoms. Often the pain has localized along the spine with irradiation to the feet. Perhaps if the child did not report the pain, the pain was, but very weak, so they could report it. Thus, in small children the pain was expressed by irritability and shrill cry, as well as sleep disturbances. Similarly, at the onset of the disease can be other symptoms, such as autonomous, i. e., fluctuating blood pressure, tachyarrhythmia and bradyarrhythmia, increased sweating etc., some of the symptoms are described below (Table I).
In the majority of the cases described in literature, in children, the evolution of the disease is monophase. Such evolution was recorded in the absolute majority of children studied, i. e., in 27 children. Usually, the first phase of GBS is the progression of clinical manifestations lasting from few days to 4 weeks. The next phase is stabilization for 4 to 8 weeks, following the phase of improvement of clinical manifestations, from 6 to 12 months. In 3 cases (10%) was determined recurrent course of disease after 1 – 2 months of improvement in symptoms. Pathological changes in cranial nerves were recorded in 2 children enrolled in study, in which develops signs of nerve damage. A weakness in the mimic muscles with the muscular strength scored by 1 and 4 points was caused by facial nerve damage. In 2 children was diagnosed unilateral damage of the mimic muscles. In 2 children was established bulbar palsy manifested by dysphonia, dysphagia and dysarthria as well as sensory disorders, in 5 children was detected shortness of breath, and in one child was found the absence of pharyngeal reflex. Also, in one child, palpebral ptosis was determined, and in one other child were determined limiting movements of the eyeballs. The motor functions are most commonly affected in the patients with GBS. Among the most common symptoms in the 30 children enrolled in study were the following: weaknesses in the limbs at the onset of the disease in most cases (93.4%) and sensory disorders manifested as sensations of burning, stinging, feeling cold in the limbs; difficulty walking and inhibition of tendon reflexes in 100% of cases; decreased muscle tone in 28 cases (93.4%), instability in the Romberg position in 63.3% cases, etc. Most children showed a significant decrease in muscle strength, according to the MRC scale, and decreased muscle tone in 93.4% cases, the absence or symmetrical decreasing of tendon reflexes in 96.7% cases. Moreover, in all children over 5 years of age, some tactile sensitivity disorders, hypoesthesia in the form of “stockings” and “gloves” were appreciated. These symptoms can not reveal in the older children of this age, because they could not express them. At 21 cases (70%) were appreciated autonomic disorders, including the following: tachycardia in 46.7% cases, fluctuating blood pressure in 26.7% cases, tachyarrhythmia in 23.3% cases, bradiarrhythmia in 13.3% cases, decreased sweating in 43.3% cases, and sphincter disorders in 2 cases (6.7%). As showing the table above, negative symptoms have been detected in most patients, and positive ones only to some of them. Diagnosis of GBS was established in 11 cases (36.7%) at the onset of the disease, in 13 cases (43.3%) – at 2 – 3 days after onset, in 6 cases (20%) over 7 – 10 days. The disease evolved with varying severity of motor disorders, i. e., mild in 10 cases (33.3%), moderate in 11 cases (36.7%), severe in 9 cases (30%). In one case the child died. The diagnosis was confirmed by lumbar puncture with the CSF exam with albuminocytological dissociation, in 84% of cases, and by the electromyographic exam with slowing down of conductance on nerve fibers, increasing of distal latencies, low motor amplitude, in 100% cases. Differential diagnosis was carried out with the following pathologies: encephalitis, acute disseminated encephalomyelitis (ADEM), poliomyelitis, spinal tumors, iatrogenic neuropathy, acute intoxication, etc. (table II). In patients enrolled in study were determined the following clinical forms of GBS: CIDP in 26 cases (86.6%), Miller-Fisher syndrome, with clinical triad, i. e., ataxia, areflexia and ophthalmoplegia in 2 cases (6.7%), acute motor sensory neuropathy in 2 cases (6.7%). Some patients received treatment by plasmapheresis (PE: 4-5 x PE (2 – 2.5 liters per procedure) (76.7%), others patients received intravenous immunoglobulin (IVIG: 0.4 g/kg for 5 days or 1 g/kg for 2 days) (23.3%). The evolution of the disease was recurrent with total or partial clinical improvement in 26 cases (86.7%), recurrence of the disease after 1 – 2 months from the relief of symptoms was recorded in 3 cases (10%), progression to death was in one case (3.3%).
Clinical case: Child aged 2.3 years, admitted in the Department of Neurology of Scientific Practial Clinic Mother and Child for the following complaints: shrill crying, irritability, sleep disorders, acute pain in the upper and lower limbs, refuses to walk, facial asymmetry, disorders of balance and convergence.
History of the disease: clinical manifestations started 2 days ago with irritability, pain in the lower limbs with crying, refusing to walk, and then the symptoms spread to the upper limbs with refusing to grasp. Clinical symptoms have progressively worsened for one day, causing development of motor deficit and affecting upper limb. 12 days ago recorded an acute respiratory infection. History of life: with no information about previous illnesses, being from the second pregnancy, the second birth, which was physiological. Neurological examination: Facial asymmetry, convergence disorders, signs of peripheral damage of the facial nerve on the right, pronounced axial hypotonia, tendon reflexes inhibited, inability to walk and maintain the body’s upright position. Investigations: CSF – Albuminocytological dissociation, ENMG – disorders of velocity and conductivity of impulse on the nerve fibers, prolongation of the conduction time of the stimulation, signs of multiple motor damage, cerebral MRI – no pathological changes, immunological tests for Borrelia burgdorferi – negative, CMV – negative, EBV – positive. Clinical diagnosis: Acute inflammatory demyelination polyneuropathy, or Miller-Fisher type. Treatment: Repeated courses of plasmapheresis (10 courses). Favorable evolution with moderate motor deficit at discharge. Partial / total recovery for one year.
DISCUSSION
In the presented material we reviewed the clinical manifestations in pediatric patients with GBS, who were admitted for 10 years in the Department of Neurology of cientific Practical Institute Mother and Child, Republic of Moldova. We found that GBS met with an increased frequency in children under 5 years of age (70 %), mainly in children between 1 and 3 years of age, and more often in boys (60%) than in girls, with the ratio of boys/girls as 1.5:1. These data correspond to the data obtained from the specialized literature [1, 8]. However, some studies in the specialty reported a higher rate of GBS syndrome in children under 5 years of age [1, 10, 11], while others reported a higher rate in children aged 5 to 10 years [1, 12, 13]. The causes of GBS are most often related to viral infections, i. e., Cytomegalovirus (CMV) in 13% of cases, Epstein Barr virus (EBV) in 10% of cases, Hepatitis E virus in 5% of cases, Zika virus (rate not known), HIV infection, Varicella Zoster, Measles virus, Influenza virus, as well as bacterial infections, i. e., Campylobacter jejuni in 32% of cases, Mycoplasma pneumoniae in 5% of cases, Lyme disease (the rate is not known), and other events, such as immunization, surgery, epidural anesthesia, Hodgkin’s disease, trauma and bone marrow transplantation [1, 8, 11, 13, 14]. However, combinations of GBS and other infections are described, including pneumococcal [14], in some cases the infection has not been identified [15], in other cases, parasitic diseases [16] are described. Children are affected by one of the infectious factors, or are exposed to some of the above causes, resulting to producing antibodies to gangliosides that trigger GBS [1, 7, 11, 14, 15]. The analysis of GBS cases, firstly, allows explaining the fact that young children are more vulnerable and prone to different respiratory and gastrointestinal infections, which are subsequently can lead to this syndrome, implicating in the pathogenesis of the disease. A second aspect of the problem can be clarified by the fact that young children have some age peculiarities, related to the immaturity of nerve structures and the increased intensity of myelination processes, which contributes to increased sensitivity of myelin to demyelination in this age group [12].
The question of why in the boys the disease is more often than in girl is reasonable, ratio B/G is 1,5:1. Perhaps, the answer related to the fact that a typical immune response to the virus is occurring in young girls, but more protein substances, i. e., antibodies, which are involved in immune process against viral or bacterial agents, are released in young boys. These immunological differences between the sexes contribute to a higher prevalence of the autoimmune processes in men than in women. Male-specific immune response is determined by the response of TH2 lymphocytes, which participates in the production of proteins from the group of IL-4, IL-5, IL-6, IL-10, and accelerate transformation of factor B. At the same time, some studies are trying to explain this difference in terms of gender difference, including genetic differences, related to different types of sex hormones in women, i. e., estrogens and progesterone, compared to those in men, i. e., testosterone [17]. According to some studies, GBS more frequently affects boys than girls; sex ratio is about 1.5 – 1.59:1 [1, 12, 13, 18]. In present study the M:F ratio is 1.5:1. A seasonal incidence was not determined in the present study. However, some authors note a higher incidence of pediatric GBS in summer, especially in July and August [8].
Among the clinical symptoms of GBS, we note:
1. muscle weakness in the lower limbs, resulting in functional inability or even paralysis;
2. tingling, numbness and sensation of needles in the legs and hands;
3. severe neuralgic pain, especially at night;
4. breathing disorders, if muscle weakness or paralysis affects the muscles involved in breathing;
5. involvement of facial muscles, including those involved in speech, chewing and swallowing;
6. vision disorders;
7. impaired bowel or bladder control;
8. abnormal heart rhythm; 9. abnormal blood pressure [1, 2, 3, 7, 8].
It was found that pain was a more frequent complaint in children, as well as bulbar dysfunction, and the severity of the disease and clinical manifestations in children were comparable to those of adults. However, the autonomous dysfunction was significantly higher in children with GBS, serving as a predictor for necessity of artificial ventilation [8]. The most common clinical manifestations in patients with GBS were lower limb weakness, neuropathic pain and the disappearance of tendon reflexes [1, 7, 8]. In literature are described very severe cases of GBS. Such a case was reported for the first time in a 13-year-old boy with a pneumococcal infection, who addressed for medical assistance himself with decreasing of activity and inability to support his own weight, following development of septic shock with acute respiratory distress syndrome, being diagnosed with GBS [14]. Another study also accentuates the importance of irritable hip pain, which could represent the initial complaint of a GBS. It show the importance of such a symptom, significant for GBS, even when all clinical and laboratory results indicate a benign condition, to avoid some potentially catastrophic consequences of more severe condition [19].
The diagnosis of GBS can be established on the basis of the criteria developed by Asbury A. K. et al. in 1978, modified in 1990 [20] (Table III). For the diagnosis of GBS it is necessary to take into consideration if the child experiences symptoms on both sides of the body, as well as the rapidity of the occurrence of symptoms, usually the onset is sudden, distal, relatively symmetrical paresthesias, quickly followed by progressive weaknesses in the limbs, likewise, if there is disappearance or loss of reflexes on the lower and upper limbs. Progression of the disease is rapid, less than 50% of cases reaching a clinical minimum for 2 weeks and over 90% – up to 4 weeks. Current diagnostic criteria include < 4 weeks of progression to clinical minimum. Approximately 80% – 90% of patients with GBS become out-ofpatient during the course of the disease [15].
Several variants of GBS were described, including [15]:
1. Acute inflammatory demyelinating polyneuropathy – AIDP, predominantly motor, bilateral facial and pharyngeal, occasionally sensory, with autonomic dysfunction;
2. Acute motor axonal neuropathy (only motor neuropathy);
3. Acute motor and sensory axonal neuropathy (motor and sensory neuropathy);
4. Miller Fisher syndrome (ophthalmoplegia, ataxia, areflexia);
5. Acute pandysautonomia (purely autonomic neuropathy, i. e., disorder both sympathetic as well as parasympathetic systems);
6. Purely sensory Guillian Barre syndrome (Purely sensory neuropathy);
7. Pharyngeal-cervical-brachial variant (motor weakness predominately with cervical brachial disorders and disorders of pharyngeal muscles);
8. Bi-brachial variant (motor weakness in both upper limbs with areflexia);
9. Distal limbs variant (limited motor weakness in distal muscles of upper and lower limbs without involvement of sensory or cranial nerves);
10. Oculopharyngeal variant (motor weakness predominantly with ocular pathology and disorders of pharyngeal muscles);
11. Paraparesis variant (muscular weakness predominantly in lower limbs);
12. Purely ophthalmoplegic variant (bilateral weakness of ocular muscles);
13. Facial paralysis with paresthesia (bilateral weakness of facial muscles with paresthesia);
14. Ropper variant (bilateral paralysis of VI and VII cranial nerves);
15. Purely generalized ataxia (symmetric axial and limb ataxia);
16. Cranial polyneuritis (cranial multiple symmetric or asymmetric neuropathy).
Thus, the symptoms are related to the clinical variant of the disease. Importantly, that the neurological signs are characterized by distal and often proximal relatively symmetrical weaknesses, sometimes accompanied by sensory dysfunction, but sensory abilities often normal at the early stage of the disease. In some cases on onset may be present asymmetric abnormalities of the muscles functions (Clinical case: a 5-year-old boy had a weakness and severe progressive pain in the lower limbs 3 days before the occurrence of unilateral peripheral facial paralysis and dysphagia. GBS confirmed by albuminocytological dissociation in CSF) [21].
In other cases may be present autonomous dysfunctions, manifested by respiratory disorders, tachycardia, arrhythmias, hypotension, hypertension, disorders of gastrointestinal dyskinesia that may be life-threating. The incidence of these complications is between 27% and 55%, and is more prevalent in the demyelinating form compared to axonal type [15, 22]. The diagnosis of GBS in the early phase can be difficult and often relies on the early clinical symptoms, i. e., progressive weakness in the lower and upper limbs, often with areflexia, which is developed within 4 weeks. It is necessary to know that in the early phase of GBS, the CSF analysis (increased level of proteins initially at 50% of cases) and EMG testing can be normal. For these reasons, for the confirmation of the diagnosis, the clinician should rely on the history of the disease and the results of the clinical examination, since increased proteins in CSF may be present at 90%, only at the peak of the disease. The early treatment of GBS have a major importance to save the patient’s life [15, 21]. Also, for the diagnosing of GBS it is necessary to carry out diagnostic tests including lumbar puncture and EMG. The EMG test, including the motor distal latency, the conductance speed of the motor nerve, the F response, the action potential of muscles, the conductance block and the conductance speed of the nerve, will show whether the function of the nerves and muscles is impaired. The authors of a study note that the anomalies of nerve conduction in the early stages of the disease are not well expressed and accentuate the importance of discovering early neurophysiological changes in patients with GBS.
They showed that the most evident parameters at the onset of GBS were the F waves, and their proportion increases in direct relation to the time elapsed after the onset. The conductance block observed mostly in the upper limbs, in about one third of the cases [19]. Other authors, who have researched the aspects of EMG in GBS confirm that the motor nerves were more affected than the sensory ones at the early stage of the disease. The abnormal values of EMG parameters was more commonly observed in the ulnar and peroneal nerve than in the median and tibial nerves, therefore it is suggested to perform a neurophysiological examination as soon as possible in patients with suspected GBS, in particular with regard to multiple investigations of ulnar and peroneal nerves [23, 24]. Were specified milestones which allow possibilities in diagnosis, namely, fever at onset, severe pulmonary dysfunction with mild weakness at the onset, severe sensory signs with mild weakness at the onset, persistent bladder or intestinal dysfunction or bladder or intestinal dysfunction at onset, impaired sensory abilities, persistently marked asymmetric weakness, increasing of the level of mononucar cells in CSF, the presence of polymorphonuclear leucocytes in CSF [15].
In such cases there should be excluded some CNS infections including HIV, CMV infection, Lyme disease, sarcoidosis, etc., but also other non-infectious diseases such as carcinomatous polyradiculopathy or lymphomatosis. One of the pathologies that require differentiation with GBS is the Multiple acyl-CoA dehydrogenation deficiency (MADD), which showed a high clinical heterogeneity with GBS, i. e., patients experienced acute weaknesses in the limbs, areflexia and sensory disorders, but the electrophysiological results and CSF are insufficient significance), what is representing a challenge for this diagnosis. The muscular biopsy performed in two patients suspected with GBS revealed lipid storage disorders and heterozygous mutations in the gene Electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH), which provided evidence for the diagnosis of lateonset MADD. Thus, taking into account the significant differences in the therapeutic regime and prognosis, the MADD should be included in the differential diagnosis of GBS [25].
At the same time, MRI imaging results can provide essential support for the differential diagnosis of GBS with other pathologies and early treatment. A retrospective study investigated the predictors of the outcome in patients with GBS, by evaluating the plasma levels of sodium, albumin and protein levels in the CSF. It was suggested that lowering the level of albumin and sodium in plasma and increasing protein levels in the CSF suggests an unfavorable outcome in patients with GBS. Elevated levels of lymphocytes and C-reactive protein, as well, indicated a worse prognosis at the end of the first month [26, 27]. A large proportion of patients are complete recovering. In this context, it is necessary to initiate timely immunological treatment after early diagnosis, which can result in a favorable prognosis for the patient [21, 28].
CONCLUSION
Acute flaccid paralysis is a common symptom of several pathologies, and its diagnosis can be difficult. The causes of GBS are variable and often related to infectious factors, suggesting the need for the application of effective immunization programs in children. GBS associates with characteristic clinical functional symptoms. Early diagnosis is often based on the history of the disease and the results of the clinical examination, i. e., early clinical symptoms such as progressive weakness in the limbs with areflexia, while CSF and EMG may be normal. Confirmation of diagnosis requires further immunological, neurophysiological and neuroimaging investigations. In the early stages of GBS it is necessary to carry out an extensive neurophysiological evaluation, with repeatedly investigation of ulnar and peroneal nerves, which often involved in the early stages of disease. The limitations of auxiliary tests in the early phase do not exclude the importance of early treatment of GBS. Elevated levels of lymphocytes in pediatric patients may be useful in the prognosis of the progression of the disease. Appropriate therapy with intravenous immunoglobulins (IVIG), is more costly, but more effective, most patients will recover very well and will result in a shorter duration of treatment in the hospital.
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