**9. Differential diagnosis**

Other immune-mediated central nervous system demyelinating disorders (clinically isolated syndrome, acute disseminated encephalomyelitis, neuromyelitis optica) must be excluded in pediatric patients presenting a first demyelinating attack.

Clinically isolated syndrome (CIS) is a monofocal (optic neuritis, brainstem syndrome, transverse myelitis, cerebellar syndrome, or hemispheric syndrome) or polyfocal clinical CNS event with a presumed inflammatory demyelinating cause without a prior clinical history of a CNS demyelinating disease and encephalopathy. MRI features do not meet McDonald's criteria. Therefore, a follow-up check for the possibility of developing MS is necessary; however, the likelihood of developing MS is low in patients with a normal brain MRI [28].

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease which is characterized by acute encephalopathy and polyfocal neurologic deficits. Encephal‐ opathy is an important feature and diagnostic criterion. Encephalopathy is defined as an alteration in consciousness or behavioral change unexplained by fever, systemic illness, or postictal symptoms in IPMSSG criteria 2012. Encephalopathy is an unexpected finding in MS. MRI features are also defined for pediatric ADEM in the 2012 IPMSSG criteria [28]. Diffuse, large (>1–2 cm), poorly demarcated hyperintense lesions are detected in cerebral white matter on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences; T1 hypointense lesions are rare and deep gray matter lesions can be present in the thalamus or basal ganglia. White matter lesions are multiple, bilateral, and asymmetrical in the cerebral hemispheres, cerebellum, brainstem, and spinal cord. Deep gray matter lesions are usually symmetrical and more characteristic of ADEM than of MS. The presence of T1 hypointense lesions in white matter leads to a diagnosis of MS. Periventricular lesions are less common. Cerebrospinal fluid (CSF) oligoclonal bands are rarely observed and usually transient in ADEM. Anti-MOG antibodies may be transiently present in the serum. ADEM is usually a monophasic disorder. Clinical and radiologic findings may fluctuate in the first 3 months after the onset of disease. A second attack of ADEM may occur rarely, and it is named "multiphasic ADEM" [28]. This second ADEM event can involve either new neurologic symptoms and MRI findings or the reemergence of prior neurologic symptoms and MRI findings. In the 2012 IPMSSG criteria, multiphasic ADEM is defined as two episodes consistent with ADEM separated by 3 months but not followed by any further events [28]. Sometimes pediatric ADEM may be the first manifestation of pediatric MS. Mikaeloff et al. showed that 18% of patients with pediatric ADEM had a second attack suggesting MS [40]. The second attack usually occurs within 2 years of the initial event.

Neuromyelitis optica (NMO) is an inflammatory disorder characterized by severe acute transverse myelitis and optic neuritis. Pediatric NMO can be monophasic or relapsing. Optic neuritis and myelitis are more severe in NMO and the prognosis is worse than it is for MS. Atypical presentations such as encephalopathy, persistent hiccups, nausea, and vomiting may occur. A brain MRI does not meet the criteria for MS and can show lesions in the supratentorial area, periaquaductal gray matter, hypothalamus, medial thalamus, dorsal pons, and medulla. The presence of longitudinally extensive spinal cord lesions (more than three vertebral segments) in a spinal MRI is an important finding and a supportive criterion. Anti-aquaporin-4 IgG seropositivity is another supportive criterion and it is 99% specific and 60–70% sensitive in children [41]. CSF oligoclonal bands are generally absent.

Other causes such as vasculitis, vascular, infectious, or neoplastic diseases must be excluded in pediatric patients with acute neurologic deficits. The presence of encephalopathy, persistent headaches, fever, polyneuropathy, and hearing loss, the involvement of other organs such as arthritis, skin rashes, oral/genital ulcers, lymphadenopathy, nephropathy, or hepatopathy with a progressive course should be suggestive of other causes. A progressive course and the involvement of the peripheral nervous system usually occur in mitochondrial diseases or neurometabolic disorders such as leukodystrophies. The diseases that should be kept in mind in the differential diagnosis are shown in **Table 1**. Markedly elevated pleocytosis, low glucose, and increased protein in CSF analysis should rouse suspicions. Persistent gadolinium en‐ hancement and continued enlargement of lesions, leptomeningeal enhancement, T2 hyperin‐ tensities in the basal ganglia, thalamus, and hypothalamus, and calcifications in an MRI should also eliminate the diagnosis of MS.

Other demyelinating disorders Clinically isolated syndrome ADEM Neuromyelitis optica Vasculitis/inflammatory diseases Primary CNS angiitis Systemic lupus erythematosus Sjögren syndrome Behcet disease

**8.2. Cerebrospinal fluid (CSF) features**

and somatosensory evoked potentials.

pediatric patients presenting a first demyelinating attack.

**9. Differential diagnosis**

children.

**8.3. Evoked potentials**

176 Trending Topics in Multiple Sclerosis

Analysis of CSF provides information about both the inflammatory process and differential diagnosis such as infection and malignancy. Cell count, presence of oligoclonal bands, and IgG index are examined in CSF analysis. A mild lymphocytic pleocystosis may be seen in children, but it has been shown that children younger than 11 years have more neutrophils in the CSF than older children. Oligoclonal band positivity has been found in 92% of patients with pediatric MS [37, 38]. An increased IgG index is more common in adolescents than in young

Evoked potentials help to demonstrate subclinical demyelination and to evaluate prior demyelination [39]. Visual evoked potentials are more informative than brainstem auditory

Other immune-mediated central nervous system demyelinating disorders (clinically isolated syndrome, acute disseminated encephalomyelitis, neuromyelitis optica) must be excluded in

Clinically isolated syndrome (CIS) is a monofocal (optic neuritis, brainstem syndrome, transverse myelitis, cerebellar syndrome, or hemispheric syndrome) or polyfocal clinical CNS event with a presumed inflammatory demyelinating cause without a prior clinical history of a CNS demyelinating disease and encephalopathy. MRI features do not meet McDonald's criteria. Therefore, a follow-up check for the possibility of developing MS is necessary; however, the likelihood of developing MS is low in patients with a normal brain MRI [28].

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease which is characterized by acute encephalopathy and polyfocal neurologic deficits. Encephal‐ opathy is an important feature and diagnostic criterion. Encephalopathy is defined as an alteration in consciousness or behavioral change unexplained by fever, systemic illness, or postictal symptoms in IPMSSG criteria 2012. Encephalopathy is an unexpected finding in MS. MRI features are also defined for pediatric ADEM in the 2012 IPMSSG criteria [28]. Diffuse, large (>1–2 cm), poorly demarcated hyperintense lesions are detected in cerebral white matter on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences; T1 hypointense lesions are rare and deep gray matter lesions can be present in the thalamus or basal ganglia. White matter lesions are multiple, bilateral, and asymmetrical in the cerebral hemispheres, cerebellum, brainstem, and spinal cord. Deep gray matter lesions are usually symmetrical and more characteristic of ADEM than of MS. The presence of T1 hypointense lesions in white matter leads to a diagnosis of MS. Periventricular lesions are less common. Cerebrospinal fluid (CSF) oligoclonal bands are rarely observed and usually transient in ADEM. Anti-MOG antibodies may be transiently present in the serum. ADEM is usually a monophasic disorder.


**Table 1.** Differential diagnosis of pediatric MS.

#### **10. Treatment**

#### **10.1. Treatment of the acute demyelinating attack**

A mildly acute demyelinating attack that does not impair the patient's functions may not require treatment. The first option in the treatment of an acute demyelinating attack is a highdose intravenous corticosteroid. Corticosteroids increase the speed of recovery and reduce the number of gadolinium-enhancing lesions on an MRI. The presumed mechanisms of action are modification of cytokine responses, reduction in T cell activation, and reduction in blood-brain barrier permeability. Intravenous corticosteroid is administered as 20–30 mg/kg (up to 1 g/ day) methyl prednisolone over 3–5 days in children. There is no consensus on tapering oral corticosteroid. Oral prednisone may be administered to patients with incomplete recovery after intravenous treatment. Plasma exchange can be considered for patients with severe, lifethreatening attacks or patients who were unresponsive to intravenous steroid treatment. The typical course is 5–7 exchanges over the course of 10–14 days. Plasma exchange therapy is an invasive treatment; its side effects include infection, blood clotting issues, and electrolyte disturbances. Another option is intravenous immunoglobulin (IVIG) if the steroids are contraindicated or the response is inadequate. There have been no controlled studies for the efficiency of this treatment in pediatric MS. IVIG influences cytokine production, T cell proliferation, and autoantibodies against myelin. It is given at a dose of 2 g/kg over 2–5 days. Side effects include fever, headache, aseptic meningitis, thromboembolism, and allergic reactions. Severe allergic reactions may develop in people with IgA deficiency; therefore, serum IgA levels should be examined before treatment [42, 43].

#### **10.2. Disease-modifying therapy**

 Neurosarcoidosis Cerebrovascular disorders

178 Trending Topics in Multiple Sclerosis

 Neurborreliosis Tuberculosis Viral encephalitis

Neurometabolic/genetic disorders Mitochondrial diseases Leukodystrophies

**Table 1.** Differential diagnosis of pediatric MS.

**10.1. Treatment of the acute demyelinating attack**

serum IgA levels should be examined before treatment [42, 43].

A mildly acute demyelinating attack that does not impair the patient's functions may not require treatment. The first option in the treatment of an acute demyelinating attack is a highdose intravenous corticosteroid. Corticosteroids increase the speed of recovery and reduce the number of gadolinium-enhancing lesions on an MRI. The presumed mechanisms of action are modification of cytokine responses, reduction in T cell activation, and reduction in blood-brain barrier permeability. Intravenous corticosteroid is administered as 20–30 mg/kg (up to 1 g/ day) methyl prednisolone over 3–5 days in children. There is no consensus on tapering oral corticosteroid. Oral prednisone may be administered to patients with incomplete recovery after intravenous treatment. Plasma exchange can be considered for patients with severe, lifethreatening attacks or patients who were unresponsive to intravenous steroid treatment. The typical course is 5–7 exchanges over the course of 10–14 days. Plasma exchange therapy is an invasive treatment; its side effects include infection, blood clotting issues, and electrolyte disturbances. Another option is intravenous immunoglobulin (IVIG) if the steroids are contraindicated or the response is inadequate. There have been no controlled studies for the efficiency of this treatment in pediatric MS. IVIG influences cytokine production, T cell proliferation, and autoantibodies against myelin. It is given at a dose of 2 g/kg over 2–5 days. Side effects include fever, headache, aseptic meningitis, thromboembolism, and allergic reactions. Severe allergic reactions may develop in people with IgA deficiency; therefore,

Progressive multifocal leukoencephalopathy (PML)

İnfection

HIV

Neoplasm

 CNS lymphoma Other CNS tumors

**10. Treatment**

The aims of treatment are to reduce disease activity, prevent disability, and preserve cognitive functions. Therefore, it is recommended to start treatment at an early stage.

First-line disease-modifying therapy includes interferon beta and glatiramer acetate. These drugs are used in adults for 15–20 years. Their efficacy, side effects, and safety are well known in adults. Both interferon beta and glatiramer acetate reduce relapse rates by approximately 30% and the accrual of new lesions on the MRI. There have been no randomized controlled trials in pediatric patients.

Glatiramer acetate is a synthetic amino acid polymer that resembles myelin basic protein. Its mechanism is not clear. It modulates T cells, shifts the population of T cells from proinflam‐ matory Th1 cells to regulatory Th2 cells, and reduces antigen presentation. Standard dosage is 20 mg daily by subcutaneous injection. Its side effects include injection reactions, lipoatrophy at injection sites, chest pain, and a post-injection reaction (anxiety, flushing, palpitations, dyspnea, and chest pain) [42–44].

Interferon beta inhibits autoreactive T cells, increases production of anti-inflammatory cytokines, reduces proinflammatory cytokines, and decreases the migration of inflammatory cells into CNS. There are two subgroups: interferon beta 1a and 1b. Interferon beta 1a is given three times a week at a dose 22 or 44 μg via subcutaneous injection or intramuscularly at a dose of 30 μg a week. A pegylated form of interferon beta 1a is used in adults, but the safety and efficacy of this form in children and adolescents have not been established. The standard dose of interferon beta-1b is 0.25 mg (8 MIU), injected subcutaneously every other day. Dose titration is recommended at the start of treatment for interferons. Most pediatric patients tolerate the adult dose. The most frequent side effects are flu-like symptoms, injection site reaction, transient transaminase elevation, bone marrow suppression, thyroid dysfunction, and depression. Paracetamol and ibuprofen are effective in managing the flu-like symptoms. Liver transaminases, blood counts, and a thyroid function test should be carried out following the treatment.

The aim of disease-modifying therapy is to reduce clinical and radiological disease activity. Disease activity is defined as clinical relapses, new or enlarging lesions on an MRI, or gadoli‐ nium-enhancing lesions on an MRI. When the first-line disease-modifying therapy remains insufficient to reduce disease activity, second-line therapies can be used. The second-line therapies that have been used in pediatric MS include natalizumab, rituximab, and cyclo‐ phosphamide [42–44].

Natalizumab is a humanized monoclonal antibody. Natalizumab selectively binds to the 4 integrin component of adhesion molecules found in lymphocytes, monocytes, eosinophils and inhibits the α4-mediated adhesion of leukocytes to their counter-receptors. It decreases clinical relapse rate by about 70% and reduces the accumulation of new or enlarging T2 hyperintense lesions. Natalizumab is given at a dose of 300 mg intravenously every 4 weeks. Its side effects include hypersensitivity and headaches. The most serious risk is progressive multifocal leukoencephalopathy (PML) in adults. This fatal risk is higher in patients who have been exposed to the JC virus and have been treated with immunosuppressive drugs previously. There is also a relationship between the duration of natalizumab therapy and an increased risk. There have been no controlled, randomized trials in pediatric MS to date.

Rituximab is a monoclonal antibody. It selectively depletes CD20+ B lymphocytes. There have been no controlled, randomized trials. Salzer et al. suggested that rituximab treatment is safe, effective, and well tolerated in their case series with pediatric MS [45].

Trials on the safety and efficacy of new oral therapies including fingolimod, dimethyl fuma‐ rate, and teriflunamide in pediatric MS patients have not been finalized.

#### **10.3. Symptomatic treatment**

Spasticity, fatigue, tremor, neuropathic pain, paroxysmal symptoms, epileptic seizures, bladder dysfunctions, and depression can be persistent symptoms in MS and affect patient's quality of life. Medical drugs can be effective in the treatment of these symptoms as in adult patients.

Baclofen, tizanidine, and benzodiazepines are effective for spasticity. Amantadine, modafinil, methylphenidate can be used for fatigue. Antiepileptic drugs such as carbamazepine, gaba‐ pentine are effective for both paroxysmal symptoms and neuropathic pain [42]. Anticholiner‐ gic agents (oxybutynin, tolterodine) can be used for detrusor hyperreflexia, and desmopressin may be beneficial for nocturia.

#### **10.4. Rehabilitation**

The aim of MS rehabilitation is to reduce symptoms including spasticity, gait disturbances, imbalance, bladder-bowel dysfunction, speech and swallowing disorders, fatigue, pain and improve quality of life. Rehabilitation interventions for MS symptoms include methods such as exercise (stretching/strengthening), gait training, endurance training, aerobic training, hydrotherapy, physiotherapy, exercise-pelvic floor training, occupational therapy, psycho‐ logical training [46]. Rehabilitation interventions should be selected according to patient's characteristics such as age and functional deficits.

Cognitive rehabilitation is an important part of MS rehabilitation, but there is no specific cognitive rehabilitation intervention for pediatric MS. Rehabilitative strategies include rehabilitation of attention and language based on other disease such as trauma, stroke, and tumor [47].
