Abstract
Objectives: To characterize MS patients with the earliest onset of disease. Background: MS—primarily a disease of young adulthood—begins in childhood in 3 to 5% of cases. However, onset before 10 years of age is considered exceptional. Accordingly, inclusion age at onset is generally between 10 and 59 years. Methods: Information was obtained on patients with MS treated at our institution (n = 6) or from reports in Medline or bibliographies. Onset of disease was before 6 years of age, for a total of 49 patients (29 girls, 20 boys). Results: All patients had clinically defined MS according to Poser’s criteria; 22 were also laboratory supported. The female/male ratio (1.4) was lower than that usually recorded for adult onset MS (2.0) and that of MS with onset between 6 and 15 years (2.2 to 3.0). The group of patients (n = 5) with onset before 24 months of age showed the lowest ratio (0.6) and carried the most unfavorable prognosis. Among initial symptoms, ataxia was preponderant (61%). Optic nerve involvement became more frequent with age. Generalized or partial seizures occurred in 22% of cases. First inter-attack interval was less than 1 year in 63% of the cases. The yearly relapse rate ranged from 1.1 at disease onset to 0.2 after 9 years from disease onset. At follow-up (mean length 6.8 years), the disease was relapsing-remitting in 84% patients and the grade of recovery was complete in 64%. Conclusions: Definite MS can be consistently diagnosed by current criteria for adult onset MS in patients with the earliest onset of disease who show peculiar clinical features and natural history. These findings may suggest a reconsideration of current lower limits for MS diagnostic criteria.
MS, an autoimmune inflammatory disease of the CNS, is primarily a disease of young adulthood with a clinical onset usually occurring between 20 and 40 years of age.1 However, in 3 to 5% of cases, MS begins before age 15.2 An onset before 10 years of age is considered exceptional,3,4 and the reported figures range from 0.21,2 to 0.7%1,5 of total scores. Accordingly, inclusion age at onset (such as for research purposes) is generally between 10 and 59 years.6 Although a broad spectrum of congenital and acquired diseases may present in childhood with similar symptoms and is often confused with MS,7,8 current radiologic and immunologic techniques make it possible to diagnose MS at a very early age.2-4,8-13 Nonetheless, many pediatricians and neurologists are unaware that this disease may occur and manifest itself even during infancy and rarely consider this diagnosis in children at this young age.14,15
Although a consistent amount of information has recently been accumulated on MS with onset between 6 and 15 years of age,2-5,8-13,16-20 no attempt has been made to classify MS with onset before 6 years of age.14,15,21-31 We selected the age of 6 years to be the divider for our research and meta-analysis on the basis of school entrance, considered as the watershed between the initial relatively limited neuromotor, cognitive, and linguistic development in infancy and toddler years and the more sophisticated range of competencies (including unfamiliar immunologic challenges) attained in middle childhood and adolescence.32 To characterize the group of MS patients with the earliest onset, we investigated the clinical, paraclinical, and neuroimaging features and outcomes of children with MS whose onset was at preschool age.
Methods.
Patients.
According to Poser’s criteria,6 MS was diagnosed in six patients (three boys and three girls) seen at the Department of Pediatrics of the University of Catania (DPUC) whose first symptoms occurred before 6 years of age,8 with the exception of the first general consideration listed in Poser’s criteria (i.e., age at onset between 10 and 59 years inclusive).6 Cranial CT (HT 8000, Philips machine) and/or MRI (0.5 and 1.0 Tesla; Philips Gyroscan), electrophysiologic studies (visual evoked potentials [VEP], brainstem auditory evoked responses [BAER], and somatosensory evoked potentials [SSEP]), and CSF analysis were performed in all patients. Neurologic disability at follow-up was scored by the Expanded Disability Status Scale33 (table 1). At present, one patient is still being monitored by a pediatric neurologist; four have moved on to adult neurologists; and one is lost to follow-up.
Clinical, laboratory and neuroimaging findings, and outcome in six children with MS
Literature review.
Published reports on MS diagnosed in patients whose first symptoms were before 6 years of age were identified by a Medline search covering the period January 1966 to August 1998. The search reviewed existing articles related to this topic and examined the reference lists of studies identified. We considered only those publications describing at least sex, age at onset, symptoms at onset and relapses, and outcome. Thirty-six articles or chapters of books met our inclusion criteria,2-5,9-15,21-31,34-46 including a case previously published by ourselves15 and not included in table 1. Reported cases with insufficient information were excluded.2,3,5,10,12,34
Data from the six patients who received follow-up at the DPUC and those from the 43 patients selected from the literature review were grouped and analyzed with the aid of the SAS program.
Results.
All of the 49 patients whose data were analyzed3,4,9,11,13-15,19,21-31,34-46 had clinically definite MS; in 22 the diagnosis was also laboratory supported according to Poser’s criteria,6 which allowed the validation of all reported cases. The main clinical, laboratory, and neuroimaging features are summarized in tables 2 and 3⇓. Other relevant features are discussed below.
Clinical features, natural history, and outcome in 49 children with MS
Laboratory findings and neuroimaging data in 49 children with MS
Age at onset.
The first episode of MS occurred between 10 and 23 months of age (n = 5) or at ages 2 (n = 15), 3 (n = 10), 4 (n = 12), and 5 (n = 7).
Family history, developmental milestones before onset, and associated diseases (number of cases where information was available = 33).
Three patients (9.6%) had a first degree relative with MS (one mother, one aunt, and one grandmother). None had remarkable associated diseases.
Initial diagnosis other than MS (number of cases where information was available = 28).
Initial diagnosis was acute disseminated encephalomyelitis (ADEM) (n = 10), isolated optic neuritis (n = 9), cerebellar ataxia (n = 7), post-traumatic event (n = 1), and cerebral neoplasm (n = 1).
Fever or illness preceding the episodes (number of cases where information was available = 39).
Patients experienced 219 separate episodes of MS. Fever or upper respiratory infections (7.3%) were noted in 16 patients preceding one of their attacks. Two other patients experienced an accidental fall during daytime activity earlier in the day of their first episode.
Symptoms of second episode same as first (number of cases where information was available = 41).
Twenty-seven patients (66%) (17 women, 10 men) had the same symptoms during their second bout.
Neurophysiology.
EEG (number of cases where information was available = 23).
In addition to patients showing an excess of slow waves diffusely (n = 5), in the posterior (n = 4) or frontal (n = 1) areas, with focal spikes (n = 4), the EEG yielded normal results (n = 9).
VEPs (number of cases where information was available = 30).
Patients had increased (n = 19), decreased (n = 3), or normal (n = 8) latencies in the affected eye.
BAER (number of cases where information was available = 18).
Patients had increased (n = 16) or normal (n = 2) latencies.
Children with ataxia.
Of the 30 children (11 boys, 19 girls) who had ataxia at onset, the clinical course was relapsing-remitting (RR) (n = 26), secondary-progressive (n = 3), or primary-progressive (n = 1). Neuroimaging showed cerebellar or brainstem lesions (n = 6), periventricular lesions (n = 10), yielded normal results (n = 5), or was not available (n = 9). MRI of the spine was never obtained during the first episode.
Children with seizures.
Of the 11 patients (8 boys, 3 girls) who had seizures9,14,21,23,24,26,36,39 (table 1), 3 (2 boys, 1 girl) (27.3%) died during the course of the disease,14,21,24 compared with 1 out of 38 patients (2.6%) who never had seizures. Eight had an RR course of disease. Mean age at onset of seizures was 6.3 years (range 2.6 to 16.2 years). Patients experienced either a single ictal episode (n = 3) or recurrent attacks (n = 8), all occurring in clinical relapses that responded well to conventional anticonvulsants. Seizures were generalized tonic-clonic (GTC) (n = 5), partial simple (PS) (n = 2), PS secondarily generalized (n = 1), PS and GTC (n = 1), or unspecified type (n = 2). The EEG showed focal spikes (n = 4) or diffuse slow waves (n = 4), or data were not given (n = 3). Patients had typical MS lesions at CT or MRI (n = 6), or neuroimaging studies were conducted but results were not provided (n = 4). MRI was not performed in one additional patient.
Treatment (number of cases where information was available = 29).
Of the 19 patients treated with high doses of oral prednisone (n = 8), IV methylprednisolone (n = 1), prednisone and methylprednisolone (not in combination) (n = 5), steroids and azathioprine (n = 1), or unspecified steroids (n = 4), a dramatic recovery of symptoms (hours to days from initial dose) was recorded in 11, equivocal benefits in 2, and no effect in 3 patients (including the patient treated with steroids and immunosoppressor); no clear information on steroids efficacy was given in 3 of the 19 patients. Clinical improvement was seen in 2 out of the 3 patients treated with corticotrophin. A spontaneous and rapid recovery was recorded in 7 patients (for a total of 25 episodes) in the absence of any specific treatment. Spontaneous clinical improvement was also recorded during a total of 16 episodes in 15 out of the 19 patients who were previously treated with steroids.
Discussion.
We report the largest group of patients with the earliest onset of MS analyzed to date.1-5,8-31,34-47 Although MS is rare in childhood, we show that no age group is immune to the disease3,4 and that peculiar clinical features characterize this subgroup of patients.
In the absence of specific guidelines, we successfully adopted the diagnostic criteria devised for adult patients6 to make a diagnosis of MS in patients at this young age. Poser’s criteria6 actually allowed for an even easier diagnosis of definite MS in our pediatric patients because their disease tends to relapse within shorter intervals than in adults (see table 2), allowing for a faster clinical confirmation of definite MS. However, it should be noted that a significant number of patients in this series were initially diagnosed with isolated optic neuritis, cerebellar ataxia, or ADEM.
The female/male preponderance that we recorded was lower (1.4) than that of adult onset MS (AOMS) (2.0)1 and that of MS patients with onset between 6 and 15 years (2.2 to 3.0)1-5,8,16,19,20,47 and was similar to that of MS appearing in the fifth decade, or later in life, which more commonly affects men.1 Notably, the lowest ratio that we recorded (0.6) was in the group of patients with age at onset younger than 24 months. This flattened ratio might be owing to the absence of early effects of sex hormones on predisposed tissues (e.g., bone marrow, CNS). Other studies also failed to demonstrate a sex prevalence in childhood MS when including MS cases with the earliest onset.1,18
The age at onset of our group of patients fits with a Gaussian distribution. Five of our 49 patients (10%) had their first symptoms before the age of 24 months14,24,27,28,37: two of them14,24 died after a rapid and severe course of the disease and a third37 had a primary progressive form. Extremely early onset of MS, then, appears to carry an unfavorable prognosis.
A positive family history for MS was less frequent (9.6%) than in previous reports of children with MS at older ages (20 to 26%)1-5,47 and adult MS patients (15%).1 In 7.3% of our patients, we recorded nonspecific infections, mostly of the upper respiratory tract, before the onset of the disease or a new relapse, thus confirming previous reports of adult patients with MS.1
Among initial symptoms ataxia was preponderant (61%) as compared with impairment of other systems (see table 2) and to the prevalence previously reported for MS with onset between 6 and 15 years (5 to 9%)8,19,47 or AOMS (7.7%) patients.1 The frequency of ataxia at onset was higher in girls (63%) than in boys. Cerebellar signs and symptoms at presentation also predominated in other series of childhood MS at older ages, although to a lesser extent.3,8,18
The recorded frequency of optic nerve involvement, especially at onset, was in keeping with other studies.1-5,8-14,16-20,34-47 However, optic neuritis was almost twice as frequent when we considered only symptoms in episodes after the first attack, suggesting that optic pathway involvement may become more common with age.
Overall, the frequency of seizures was higher (22%) than in childhood MS with onset above age 6 years (10%) and in (2 to 5%) patients with AOMS.1 This significant occurrence may be characteristic of MS patients with the earliest onset of disease or may merely reflect the increased and nonspecific likelihood of seizures in this MS age group as a result of widespread involvement of the CNS. However, 27% of our patients with seizures had a more aggressive clinical course and died. Accordingly, in this age group, seizures represent an unfavorable prognostic factor.
In this age group, the first occurrence of MS appeared to affect the patient’s general status much more than in other age groups and was commonly associated with lethargy or coma, vomiting, or seizures. Despite this greater systemic involvement, recovery time was shorter (4 weeks) compared with what has been reported for older children with MS (5 to 6 weeks) and patients with AOMS (6 to 8 weeks).1-4 Boys recovered faster than girls, an occurrence not previously reported1-5,8-14,16-20,34-47 and of uncertain meaning. Disability after the initial episode was rare and mild.
Most patients had their second exacerbation within 1 year (63%), differing from that of older age groups. The overall course in this age group was less aggressive than classic adult MS (see table 2). Girls relapsed faster and less frequently than boys. However, a subgroup of patients with the earliest onset of MS might be particularly prone to the pathologic changes of the disease: 4 of the 43 reported infants (9.3%), in fact, died as a result of a relapse, a previously unreported observation in childhood MS.1,3,13
Laboratory features were broadly in keeping with previous large childhood MS series,2-4,8-14,16-20,34-47 showing pleiocytosis and high protein levels in the CSF and an increasing rate of positivity for oligoclonal bands with disease progression (see table 3). Interestingly, epileptic discharges were detected in only 50% of children with seizures where information on EEGs was provided. MRI proved to be the preferred method of investigation on the grounds of sensitivity and noninvasiveness (see table 3). However, MRI is not available worldwide and requires appropriate sedation for younger children, which is generally not necessary for CT scanning. Although CT scan is still valuable in the common clinical evaluation in infants and toddlers with acute neurologic disorders, its value in assessing potential childhood MS is low. In the 43 reported children, CT scan showed a high rate of false-negatives (see table 3) when used as the first neuroimaging tool or during further attacks of the disease.
No controlled studies on the treatment of MS in childhood have been reported so far. Current therapy in children with MS follows the same guidelines used in adult neurology. Notably, some of the reported cases at this young age and most of our patients (see table 1) experienced faster neurologic recovery or a shorter duration of acute relapses by using steroids. Short courses (3 to 5 days) of high doses (500 or 1,000 mg in children over 10 years of age) of IV methylprednisolone were considered in the group of patients seen at DPUC (see table 1) to be most beneficial. Corticotrophin was never used in our experience of treatment of exacerbations. More frequent relapses were recorded on steroids withdrawal, and steroids were ineffective in those children having a chronic progression of disease. However, children with MS in this age group rapidly remitted even without therapy, further suggesting that preschool MS is usually more benign than AOMS, at least in the initial decade after disease onset.
Acknowledgments
Acknowledgment
The authors wish to thank Dr. Jackie Palace (Oxford University, UK) for reviewing the manuscript and for her helpful suggestions and discussion. Ian Halliday is gratefully acknowledged for editing the final draft of the manuscript.
Footnotes
-
Dr. Grimaldi is supported by the Armenise-Harvard Foundation.
-
Presented in part at the Eighth International Child Neurology Association Congress; September 1998; Ljubljana, Slovenia; and published in abstract form in Brain Dev 1998;20:430–431.
- Received August 10, 1998.
- Accepted March 13, 1999.
References
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