Therapies recommended are mainly immunomodulating agents targeting the immunebased mechanism of the disease. Corticosteroids are considered the mainstay of treatment based on the rapid improvement in symptoms following therapy (Straub *et al*., 1997;, Tenembaum *et al*., 2007). However widely varying doses, formulations, duration of therapy and tapering have been reported with corticosteroid use (Hynson *et al*., 2001; Murthy *et al*., 2002; Tenembaum *et al*., 2007; Govender *et al*., 2010). A single study reported worse outcomes in patients who received corticosteroids (Boe *et al*., 1965). Methylprednisone, dexamethasone and ACTH are used. Most reports in paediatric patients have used IV methylprednisolone (10 to 30 mg/kg/day) or dexamethasone (1 mg/kg) for 3 to 5 days (Dale *et al*., 2000; Hyson *et al* 2001; Tenembaum *et al* 2002; Govender *et al*., 2010) followed by a taper for 4 to 6 weeks with full recovery reported in 50 to 80% of patients. In resource poor countries high dose corticosteroids must be used with caution and only commenced once commonly occurring infections like tuberculosis and cytomegalovirus (CMV) are excluded. Outcomes on efficacy of corticosteroid treatment are mainly compared to historical controls. Worse outcomes are linked to shorter duration of treatment (Tenembaum *et al*., 2007). Other treatment modalities suggested include intravenous immunoglobulin, plasmapheresis and glatiramer acetate (Abramsky *et al*., 1977; Stricker *et al*., 1992; Finsterer *et al*., 1998). There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulin if they fail to respond to either separately

ADEM is by definition a monophasic illness (variants are discussed in Section 4.8). Mortality during the post-measles ADEM period in the 1950's was reported as 10-30% (Johnson *et al.*, 1985). At follow-up, approximately 60-80% of children have no neurologic deficits (Menge *et al*., 2007). This study also reports a mortality rate of 5%. The extent and site of lesions on the initial MRI do not predict the clinical outcome. Motor deficits persist in 8-30% (Dale *et al.,* 2000; Tenembaum *et al.,* 2007) of patients and include paraparesis, hemiparesis and ataxia. Neuro-cognitive deficits are also documented post ADEM (Hahn *et al.,* 2003; Jacobs *et* al., 2004). These include deficits in short term memory, verbal processing skills and complex attention. Patient with early onset ADEM (<5year of age) were also more likely to have cognitive deficits and behaviour problems (Kumar *et al*., 1998). Follow-up MRI's showed complete or partial resolution of abnormalities in the majority of cases (Kesslering *et a*l., 1990; Dale *et al*., 2000; Tenembaum *et al* 2007; Govender *et al*., 2010). However, residual gliosis and demyelination persist in some patients (Kesselring *et al*., 1990). Clinical as well as imaging follow-up (at least 3 months later) **(Figure 6)** is important to monitor for evolution

to MS. Risk factors for relapse are discussed in greater detail in Section 10.

Definitions for Recurrent and Multi-phasic ADEM are described in Table 1.

Acute Hemorrhagic Leukoencephalitis is a rare, hyper-acute form of ADEM with a mortality rate of about 70% (Davies *et al*., 2006). Pathological studies show a necrotizing vasculitis

brainstem involvement, anti-epileptics for seizure control) in the acute phase is vital.

**4.6 Treatment**

(Straussberg *et al*., 2001).

**4.8 Variants of ADEM**

**4.7 Prognosis**

Fig. 4. T1 with contrast axial MRI demonstrating multiple hypo-intense white matter lesions of varying sizes, some with ring enhancement. This patient was diagnosed with ADEM.

Fig. 5. A- T2 sagittal MRI of the cord showing diffuse abnormal high signal intensity throughout the cord with cord expansion in the cervical region. There was no associated enhancement. This together with the brain lesions seen in 5B is consistent with ADEM. B-Flair axial MRI demonstrating bilateral high signal intensity lesions in the basal ganglia and deep white matter on the left consistent with ADEM.

#### **4.6 Treatment**

68 Neuroimaging – Clinical Applications

Fig. 4. T1 with contrast axial MRI demonstrating multiple hypo-intense white matter lesions of varying sizes, some with ring enhancement. This patient was diagnosed with ADEM.

 A B Fig. 5. A- T2 sagittal MRI of the cord showing diffuse abnormal high signal intensity throughout the cord with cord expansion in the cervical region. There was no associated enhancement. This together with the brain lesions seen in 5B is consistent with ADEM. B-Flair axial MRI demonstrating bilateral high signal intensity lesions in the basal ganglia and

deep white matter on the left consistent with ADEM.

There are no standard treatment protocols as there are insufficient large scale studies to form consensus for optimal management. Supportive care (e.g. respiratory support for patients with brainstem involvement, anti-epileptics for seizure control) in the acute phase is vital.

Therapies recommended are mainly immunomodulating agents targeting the immunebased mechanism of the disease. Corticosteroids are considered the mainstay of treatment based on the rapid improvement in symptoms following therapy (Straub *et al*., 1997;, Tenembaum *et al*., 2007). However widely varying doses, formulations, duration of therapy and tapering have been reported with corticosteroid use (Hynson *et al*., 2001; Murthy *et al*., 2002; Tenembaum *et al*., 2007; Govender *et al*., 2010). A single study reported worse outcomes in patients who received corticosteroids (Boe *et al*., 1965). Methylprednisone, dexamethasone and ACTH are used. Most reports in paediatric patients have used IV methylprednisolone (10 to 30 mg/kg/day) or dexamethasone (1 mg/kg) for 3 to 5 days (Dale *et al*., 2000; Hyson *et al* 2001; Tenembaum *et al* 2002; Govender *et al*., 2010) followed by a taper for 4 to 6 weeks with full recovery reported in 50 to 80% of patients. In resource poor countries high dose corticosteroids must be used with caution and only commenced once commonly occurring infections like tuberculosis and cytomegalovirus (CMV) are excluded. Outcomes on efficacy of corticosteroid treatment are mainly compared to historical controls. Worse outcomes are linked to shorter duration of treatment (Tenembaum *et al*., 2007). Other treatment modalities suggested include intravenous immunoglobulin, plasmapheresis and glatiramer acetate (Abramsky *et al*., 1977; Stricker *et al*., 1992; Finsterer *et al*., 1998). There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulin if they fail to respond to either separately (Straussberg *et al*., 2001).

#### **4.7 Prognosis**

ADEM is by definition a monophasic illness (variants are discussed in Section 4.8). Mortality during the post-measles ADEM period in the 1950's was reported as 10-30% (Johnson *et al.*, 1985). At follow-up, approximately 60-80% of children have no neurologic deficits (Menge *et al*., 2007). This study also reports a mortality rate of 5%. The extent and site of lesions on the initial MRI do not predict the clinical outcome. Motor deficits persist in 8-30% (Dale *et al.,* 2000; Tenembaum *et al.,* 2007) of patients and include paraparesis, hemiparesis and ataxia. Neuro-cognitive deficits are also documented post ADEM (Hahn *et al.,* 2003; Jacobs *et* al., 2004). These include deficits in short term memory, verbal processing skills and complex attention. Patient with early onset ADEM (<5year of age) were also more likely to have cognitive deficits and behaviour problems (Kumar *et al*., 1998). Follow-up MRI's showed complete or partial resolution of abnormalities in the majority of cases (Kesslering *et a*l., 1990; Dale *et al*., 2000; Tenembaum *et al* 2007; Govender *et al*., 2010). However, residual gliosis and demyelination persist in some patients (Kesselring *et al*., 1990). Clinical as well as imaging follow-up (at least 3 months later) **(Figure 6)** is important to monitor for evolution to MS. Risk factors for relapse are discussed in greater detail in Section 10.

#### **4.8 Variants of ADEM**

Definitions for Recurrent and Multi-phasic ADEM are described in Table 1.

Acute Hemorrhagic Leukoencephalitis is a rare, hyper-acute form of ADEM with a mortality rate of about 70% (Davies *et al*., 2006). Pathological studies show a necrotizing vasculitis

Acquired Demyelinating Disorders of the CNS in Children 71

Clinical presentation is that of acute or sub-acute onset of bilateral spinal cord dysfunction (that may be asymmetrical) with associated sphincter dysfunction and pain. A sensory level may not be easily elicitable in the paediatric population. The clinical features depend on the location of the lesion. High cervical cord lesions can present with respiratory failure. The thoracic segment is the commonest site of cord involvement in ATM (Kneubusch *et al*., 1998).

Initial evaluation of a patient with an evolving myelopathy must include a gadolinium enhanced MRI of the spine to exclude a compressive myelopathy. If there is no evidence of a compressive lesion a lumbar puncture should be performed. CSF pleocytosis and an elevated protein (IgG index) on the CSF support a diagnosis of ATM. Brain MRI and eye examination with visual evoked potentials are recommended to exclude demyelination in

Other investigations recommended include para-infectious markers- EBV, VZV, CMV, Herpes Simplex virus serology and stool for campylobacter cultures. If there are signs of a systemic inflammatory disorder, auto-immune screens and serum angiotensin converting enzyme levels should be performed to exclude other causes of an acute myelopathy (e.g. vasculitides).

 A B C D E Fig. 7. A- T2 sagittal MRI of the cord showing diffuse abnormal increased signal intensity consistent with transverse myelitis. B- T1 sagittal MRI of the cord showing no abnormal signal intensity. There was no contrast enhancement. C- T2 sagittal MRI of the distal cord showing diffuse abnormal increased signal intensity consistent with transverse myelitis. D-T2 axial MRI of the cord showing abnormal increased signal intensity consistent with transverse myelitis. E- T2 sagittal MRI of the cord showing diffuse abnormal increased

signal intensity and cord swelling consistent with transverse myelitis.

**5.3 Clinical presentation**

**5.4 Investigations**

other parts of the neuro-axis.

with haemorrhage, oedema and a neutrophilic infiltration (Stone and Hawkins, 2007). Seventy percent of survivors have neurological deficits (Stone and Hawkins, 2007).

Fig. 6. A- T2 axial MRI demonstrating asymmetrical basal ganglia and white matter high signal intensities consistent with ADEM. B- T2 axial MRI in same patient at 3 months followup showing resolution of lesions.

#### **5. Transverse myelitis**

#### **5.1 Epidemiology**

Acute Transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord resulting in motor, sensory and autonomic dysfunction with evidence of inflammation on CSF or MRI studies. The initial definition was proposed by the Transverse Myelitis Consortium Working Group in 2002 and refined by the more recent consensus definitions for paediatric demyelinating disease (Krupp *et al*., 2007). The incidence is reported as 1- 8 per million people per year (Berman *et al*., 1981). There are no gender or ethnic differences in the prevalence of ATM (Berman *et al*., 1981). ATM is often difficult to distinguish clinically from ischaemic cord lesions, fibro-cartilagenous emboli or traumatic spinal cord lesions. ATM is also an important differential diagnosis for acute flaccid paralysis in childhood.

#### **5.2 Pathogenesis**

The aetiology of ATM is thought to be immune-mediated. In 30-60% of patients ATM is para-infectious (Jeffrey *et al*., 1993; Kalra *et al*., 2009). Molecular mimicry and super-antigen mediated mechanisms have been postulated (Kaplin *et al*., 2005). Positive anti-GM1 antibodies following Campylobacter and CMV infections have been implicated in the aetiopathogenesis. Neuromyelitis optica—immunoglobulin G is an aquaporin-4–specific water channel antibody, which has been associated with neuromyelitis optica and longitudinally extensive transverse myelitis in adults (Lennon *et al*., 2004). This is discussed further in Section 6.

#### **5.3 Clinical presentation**

70 Neuroimaging – Clinical Applications

with haemorrhage, oedema and a neutrophilic infiltration (Stone and Hawkins, 2007).

Seventy percent of survivors have neurological deficits (Stone and Hawkins, 2007).

A B

up showing resolution of lesions.

**5. Transverse myelitis**

**5.1 Epidemiology**

**5.2 Pathogenesis**

Section 6.

Fig. 6. A- T2 axial MRI demonstrating asymmetrical basal ganglia and white matter high signal intensities consistent with ADEM. B- T2 axial MRI in same patient at 3 months follow-

Acute Transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord resulting in motor, sensory and autonomic dysfunction with evidence of inflammation on CSF or MRI studies. The initial definition was proposed by the Transverse Myelitis Consortium Working Group in 2002 and refined by the more recent consensus definitions for paediatric demyelinating disease (Krupp *et al*., 2007). The incidence is reported as 1- 8 per million people per year (Berman *et al*., 1981). There are no gender or ethnic differences in the prevalence of ATM (Berman *et al*., 1981). ATM is often difficult to distinguish clinically from ischaemic cord lesions, fibro-cartilagenous emboli or traumatic spinal cord lesions. ATM is also an important differential diagnosis for acute flaccid paralysis in childhood.

The aetiology of ATM is thought to be immune-mediated. In 30-60% of patients ATM is para-infectious (Jeffrey *et al*., 1993; Kalra *et al*., 2009). Molecular mimicry and super-antigen mediated mechanisms have been postulated (Kaplin *et al*., 2005). Positive anti-GM1 antibodies following Campylobacter and CMV infections have been implicated in the aetiopathogenesis. Neuromyelitis optica—immunoglobulin G is an aquaporin-4–specific water channel antibody, which has been associated with neuromyelitis optica and longitudinally extensive transverse myelitis in adults (Lennon *et al*., 2004). This is discussed further in Clinical presentation is that of acute or sub-acute onset of bilateral spinal cord dysfunction (that may be asymmetrical) with associated sphincter dysfunction and pain. A sensory level may not be easily elicitable in the paediatric population. The clinical features depend on the location of the lesion. High cervical cord lesions can present with respiratory failure. The thoracic segment is the commonest site of cord involvement in ATM (Kneubusch *et al*., 1998).

#### **5.4 Investigations**

Initial evaluation of a patient with an evolving myelopathy must include a gadolinium enhanced MRI of the spine to exclude a compressive myelopathy. If there is no evidence of a compressive lesion a lumbar puncture should be performed. CSF pleocytosis and an elevated protein (IgG index) on the CSF support a diagnosis of ATM. Brain MRI and eye examination with visual evoked potentials are recommended to exclude demyelination in other parts of the neuro-axis.

Other investigations recommended include para-infectious markers- EBV, VZV, CMV, Herpes Simplex virus serology and stool for campylobacter cultures. If there are signs of a systemic inflammatory disorder, auto-immune screens and serum angiotensin converting enzyme levels should be performed to exclude other causes of an acute myelopathy (e.g. vasculitides).

Fig. 7. A- T2 sagittal MRI of the cord showing diffuse abnormal increased signal intensity consistent with transverse myelitis. B- T1 sagittal MRI of the cord showing no abnormal signal intensity. There was no contrast enhancement. C- T2 sagittal MRI of the distal cord showing diffuse abnormal increased signal intensity consistent with transverse myelitis. D-T2 axial MRI of the cord showing abnormal increased signal intensity consistent with transverse myelitis. E- T2 sagittal MRI of the cord showing diffuse abnormal increased signal intensity and cord swelling consistent with transverse myelitis.

Acquired Demyelinating Disorders of the CNS in Children 73

The Mayo Clinic proposed a revised set of criteria in 2006. The new guidelines for diagnosis requires both absolute criteria and two of the three supportive criteria to be present to make

2. Spinal cord MRI showing contiguous T2-weighted signal abnormality extending over 3 or more vertebral segments, indicating a relatively large lesion in the spinal cord

The association of NMO with the serum autoantibody marker NMO-IgG was reported in 2004 (Lennon *et al.,* 2004). NMO-IgG is 73% sensitive and 91% specific for distinguishing NMO from classical MS. The new diagnostic criteria allows for the diagnosis of NMO in patients who are NMO-IgG antibody negative. NMO antibodies play a key role in the pathogenesis. These antibodies are directed against the aquaporin-4- receptors located in the cell membrane of astrocytes (Pearce, 2005). Aquaporin-4 is the most abundant channel facilitating water transport across membranes in the brain. NMO-IgG is also detected more commonly in patients with NMO symptoms who have clinical or serological evidence for

Clinical characteristics include painful visual loss, weakness, sphincter dysfunction and sensory deficits. Loss of red color vision, a relative afferent pupillary defect and visual field defects are other features of optic neuritis in children. Other complications such as ataxia and respiratory failure result from extension of cervical cord lesions into the brainstem.

Diagnostic evaluation includes an MRI of the brain. During acute optic neuritis attacks, an orbital MRI may identify optic nerve gadolinium-enhancement. MRI of the brain is usually normal. However, brain lesions located in the hypothalamus, brainstem, and periventricular areas have been described in children who have typical features of NMO (Pittock *et al*.,

Patients with signs of myelitis should have a spinal MRI with contrast. The lesions are typically longitudinally extensive, centrally based in the cord and extend over three or more vertebral segments. All patients should have a serological test for the NMO-IgG antibody. A negative test however does not exclude the diagnosis. CSF pleocytosis also supports the diagnosis. In patients with longitudinal myelitis and no visual symptoms, visual evoked

The recommended treatment for acute attacks of myelitis or optic neuritis is high dose methylprednisone. Prophylactic long-term immunosuppression is recommended for established NMO and patients who have a single attack of myelitis and are NMO-IgG positive (Wingerchuck *et al*., 2005). There are no efficacious preventative therapies demonstrated by controlled trials in NMO. Intravenous immunoglobulin is an alternative

2005). These are considered to be the aquaporin-4 rich areas of the brain.

potentials can sometimes detect asymptomatic visual pathway dysfunction.

a diagnosis of NMO (Wingerchuck *et al*., 2006).

3. NMO-IgG seropositive status.

**6.1 Clinical characteristics**

**6.2 Investigations**

**6.3 Treatment**

1. Brain MRI not meeting criteria for MS at disease onset

SLE than in those who do not (McAdam *et al*., 2002).

for patients who do not respond to corticosteroids.

Absolute criteria: 1. Optic neuritis 2. Acute myelitis Supportive criteria:

#### **5.5 Neuro-imaging**

MRI of the spinal cord usually shows nonspecific localized hyper-intense signal on T2WI sequences with, in some cases, segmental cord enlargement and/or focal enhancement **(Figure 7 a-e).** Acute partial transverse myelitis described in adults is characterized by MRI lesions that are asymmetrically placed and spanning fewer than 2 vertebral segments in length; these patients have been found to have a greater risk of progression to multiple sclerosis (Ford *et al*., 1992). Longitudinally extensive myelitis (spanning > 3 vertebral segments) is shown to have a lower risk of progression to MS in adults (Pittock *et al*, 2006). Lesions of ATM in children are typically longitudinal, demonstrate rim enhancement and are centrally located.

#### **5.6 Treatment**

Previous case series did not demonstrate any benefit from the use of low dose corticosteroids (Dunn *et a*l., 1986; Adams *et al*., 1990). Recent reports demonstrate the benefit of high dose corticosteroids (10-30mg/kg per day for 3-5 days) on recovery (Defrense *et al*., 2001; Sebire *et al*., 1997). Compared to historical controls patients treated with steroids walked independently sooner. If there is no clinical response to steroids within 5-7 days plasma exchange was used as adjunctive therapy in isolated case reports. Supportive measures include respiratory support and early management of a neuropathic bladder.

#### **5.7 Prognosis**

Various studies have looked at prognostic indicators for ATM. Jain *et al*. (1983) described backache at onset, acute course (within hours), spinal shock and a cervical sensory level as poor prognostic features. Other studies did not demonstrate this (Govender *et al*., 2010). Early recovery (within one week of presentation), age less than 10 years at presentation and lumbosacral spinal level on clinical assessment were significant predictors of a good outcome (De Goede *et al*., 2010). The extent of lesions on MRI has not shown consistent correlation with outcome (Pradhan *et al*., 1997; Adronikou *et al.,* 2003). Berman *et al's* series (1987) described more than one-third of the patients with ATM making a good recovery; in one-third of patients recovery was only fair; 14 patients failed to improve and 3 demised. In the series by Dunne *et al* (1986) that assessed the risk of progression to multiple sclerosis in children with ATM, definite evidence of multiple sclerosis did not develop in any of the patients. In the series by Pidcock *et al* of the 47 children with acute transverse myelitis, 2 experienced recurrent transverse myelitis, 1 was diagnosed with neuromyelitis optica, and 1

#### **6. Neuromyelitis Optica (NMO)**

developed multiple sclerosis on follow-up (Pidcock *et al*., 2007).

The association between myelitis and optic problems was first described in 1870 by Thomas Clifford Allbutt (Murray, 2005). In 1894 Eugene Devic described 16 patients with visual impairment who developed paraparesis, sensory deficits and sphincter dysfunction within weeks. They recognized that these symptoms were the result of inflammation of the optic nerve and spinal cord. NMO is a recurrent demyelinating disorder affecting the optic nerves and the spinal cord. Modifications to the definition of NMO in 2005 incorporated the inclusion of patients with brain lesions, and included the NMO-IgG antibody as a confirmatory test.

The Mayo Clinic proposed a revised set of criteria in 2006. The new guidelines for diagnosis requires both absolute criteria and two of the three supportive criteria to be present to make a diagnosis of NMO (Wingerchuck *et al*., 2006).

Absolute criteria:

72 Neuroimaging – Clinical Applications

MRI of the spinal cord usually shows nonspecific localized hyper-intense signal on T2WI sequences with, in some cases, segmental cord enlargement and/or focal enhancement **(Figure 7 a-e).** Acute partial transverse myelitis described in adults is characterized by MRI lesions that are asymmetrically placed and spanning fewer than 2 vertebral segments in length; these patients have been found to have a greater risk of progression to multiple sclerosis (Ford *et al*., 1992). Longitudinally extensive myelitis (spanning > 3 vertebral segments) is shown to have a lower risk of progression to MS in adults (Pittock *et al*, 2006). Lesions of ATM in children are typically longitudinal, demonstrate rim enhancement and

Previous case series did not demonstrate any benefit from the use of low dose corticosteroids (Dunn *et a*l., 1986; Adams *et al*., 1990). Recent reports demonstrate the benefit of high dose corticosteroids (10-30mg/kg per day for 3-5 days) on recovery (Defrense *et al*., 2001; Sebire *et al*., 1997). Compared to historical controls patients treated with steroids walked independently sooner. If there is no clinical response to steroids within 5-7 days plasma exchange was used as adjunctive therapy in isolated case reports. Supportive measures include respiratory support and early management of a neuropathic bladder.

Various studies have looked at prognostic indicators for ATM. Jain *et al*. (1983) described backache at onset, acute course (within hours), spinal shock and a cervical sensory level as poor prognostic features. Other studies did not demonstrate this (Govender *et al*., 2010). Early recovery (within one week of presentation), age less than 10 years at presentation and lumbosacral spinal level on clinical assessment were significant predictors of a good outcome (De Goede *et al*., 2010). The extent of lesions on MRI has not shown consistent correlation with outcome (Pradhan *et al*., 1997; Adronikou *et al.,* 2003). Berman *et al's* series (1987) described more than one-third of the patients with ATM making a good recovery; in one-third of patients recovery was only fair; 14 patients failed to improve and 3 demised. In the series by Dunne *et al* (1986) that assessed the risk of progression to multiple sclerosis in children with ATM, definite evidence of multiple sclerosis did not develop in any of the patients. In the series by Pidcock *et al* of the 47 children with acute transverse myelitis, 2 experienced recurrent transverse myelitis, 1 was diagnosed with neuromyelitis optica, and 1

The association between myelitis and optic problems was first described in 1870 by Thomas Clifford Allbutt (Murray, 2005). In 1894 Eugene Devic described 16 patients with visual impairment who developed paraparesis, sensory deficits and sphincter dysfunction within weeks. They recognized that these symptoms were the result of inflammation of the optic nerve and spinal cord. NMO is a recurrent demyelinating disorder affecting the optic nerves and the spinal cord. Modifications to the definition of NMO in 2005 incorporated the inclusion of patients with brain lesions, and included the NMO-IgG antibody as a

developed multiple sclerosis on follow-up (Pidcock *et al*., 2007).

**6. Neuromyelitis Optica (NMO)**

confirmatory test.

**5.5 Neuro-imaging**

are centrally located.

**5.6 Treatment**

**5.7 Prognosis**

Supportive criteria:

The association of NMO with the serum autoantibody marker NMO-IgG was reported in 2004 (Lennon *et al.,* 2004). NMO-IgG is 73% sensitive and 91% specific for distinguishing NMO from classical MS. The new diagnostic criteria allows for the diagnosis of NMO in patients who are NMO-IgG antibody negative. NMO antibodies play a key role in the pathogenesis. These antibodies are directed against the aquaporin-4- receptors located in the cell membrane of astrocytes (Pearce, 2005). Aquaporin-4 is the most abundant channel facilitating water transport across membranes in the brain. NMO-IgG is also detected more commonly in patients with NMO symptoms who have clinical or serological evidence for SLE than in those who do not (McAdam *et al*., 2002).

#### **6.1 Clinical characteristics**

Clinical characteristics include painful visual loss, weakness, sphincter dysfunction and sensory deficits. Loss of red color vision, a relative afferent pupillary defect and visual field defects are other features of optic neuritis in children. Other complications such as ataxia and respiratory failure result from extension of cervical cord lesions into the brainstem.

#### **6.2 Investigations**

Diagnostic evaluation includes an MRI of the brain. During acute optic neuritis attacks, an orbital MRI may identify optic nerve gadolinium-enhancement. MRI of the brain is usually normal. However, brain lesions located in the hypothalamus, brainstem, and periventricular areas have been described in children who have typical features of NMO (Pittock *et al*., 2005). These are considered to be the aquaporin-4 rich areas of the brain.

Patients with signs of myelitis should have a spinal MRI with contrast. The lesions are typically longitudinally extensive, centrally based in the cord and extend over three or more vertebral segments. All patients should have a serological test for the NMO-IgG antibody. A negative test however does not exclude the diagnosis. CSF pleocytosis also supports the diagnosis. In patients with longitudinal myelitis and no visual symptoms, visual evoked potentials can sometimes detect asymptomatic visual pathway dysfunction.

#### **6.3 Treatment**

The recommended treatment for acute attacks of myelitis or optic neuritis is high dose methylprednisone. Prophylactic long-term immunosuppression is recommended for established NMO and patients who have a single attack of myelitis and are NMO-IgG positive (Wingerchuck *et al*., 2005). There are no efficacious preventative therapies demonstrated by controlled trials in NMO. Intravenous immunoglobulin is an alternative for patients who do not respond to corticosteroids.

Acquired Demyelinating Disorders of the CNS in Children 75

A B C

D E F

lesion will have a brain biopsy mainly to exclude other disorders.

**7.3 Treatment**

Fig. 8. A & B – T2 axial MRI demonstrating multiple well-defined hyper-intense white matter foci surrounded by more ill-defined areas of increased white matter signal intensity consistent with Schilder's Disease. C- Flair axial MRI demonstrating multiple hyper-intense lesions of varying sizes within the white matter with some areas of suppression within the plaques consistent with Schilder's Disease. D- Flair parasagittal MRI demonstrating large flame- shaped white matter plaque with some areas of suppression within the lesions consistent with Schilder's Disease. E & F- T1 with contrast axial MRI demonstrating multiple non- enhancing hypo-intense lesions of varying shapes and sizes within the white matter.

Other supportive diagnostic tests include an elevated CSF protein and an elevation of CSF IgG in 50-60% of patients with Schilder's Disease. Many patients with a large ring enhancing

The treatment of choice is high dose intravenous corticosteroids. A rapid clinical and radiological response to high dose corticosteroids favors the diagnosis of demyelination.

Characteristics of NMO that help to distinguish it from classical MS include:

#### **7. Schilder's disease/myelinoclastic diffuse sclerosis**

This disorder was initially described by Schilder in 1912 and later clarified by Poser (1992). There are further reported cases of solitary, large plaque like lesions, which were histologically confirmed to be foci of demyelination (Kumar *et al*., 1998; Gutling and Landis, 1998). The aetiology is unclear; however an association with tuberculosis was described in 3 South African children (Pretorius *et al.,* 1998). Schilder's Disease occurs predominantly in children (peak age 5-14 years) (Afifi *et al*., 1994).

The Poser criteria (1992) for diagnosis are:

#### **7.1 Clinical presentation**

The clinical presentation is non-specific and includes neuroregression, seizures, ataxia or signs of raised intra-cranial pressure.

#### **7.2 Neuro-imaging**

The lesions of Schilder's Disease are typically large and plaque-like and have also been termed tumefactive demyelination. MRI is the most accurate modality of delineating the lesions that are often confused with brain neoplasms or abscesses. Making the distinction between demyelination and infection/malignancies early is important to prevent unnecessary surgical procedures and toxic therapies like radiation and chemotherapy (McAdam *et al.,* 2002). MRI studies demonstrate 1 or 2 large confluent lesions in the deep white matter, usually the centrum semiovale **(Figure 8 a-f).** Lesions are at least 2 cm in size in 2 of 3 dimensions. No additional lesions should be observed on imaging of the brain or spinal cord- this would suggest MS or ADEM. On T1WI, tumefactive demyelination lesions reveal a hypo-intense central area with a thick surrounding band of moderately increased intensity. Lesions are centrally hyper-intense on T2WI. Enhancement, when present, is incomplete. The lesions are characterized by enhancement limited to one side of the lesion; usually the rim facing the lateral ventricles (McAdam *et al*., 2007). Demyelination can be distinguished from other ring enhancing lesions (brain abscesses, tumors, parasitic infections) by the presence of other demyelinating plaques elsewhere in the central nervous system.

Prominent CSF pleocytosis (more than 50 WBC) with a polymorphonuclear cell

Lower frequency of CSF oligoclonal banding (15-30% in NMO compared to 85% in MS)

At disease onset, the brain MRI scan is normal or reveals nonspecific white matter

 MRI of the spinal cord showing longitudinally extensive, central lesions (MS lesions are more peripherally located in the cord and extend over one to two segments in length)

This disorder was initially described by Schilder in 1912 and later clarified by Poser (1992). There are further reported cases of solitary, large plaque like lesions, which were histologically confirmed to be foci of demyelination (Kumar *et al*., 1998; Gutling and Landis, 1998). The aetiology is unclear; however an association with tuberculosis was described in 3 South African children (Pretorius *et al.,* 1998). Schilder's Disease occurs predominantly in

pathological analysis is consistent with sub-acute or chronic myelinoclastic diffuse

adrenoleukodystrophy and peripheral nervous system involvement must be excluded.

The clinical presentation is non-specific and includes neuroregression, seizures, ataxia or

The lesions of Schilder's Disease are typically large and plaque-like and have also been termed tumefactive demyelination. MRI is the most accurate modality of delineating the lesions that are often confused with brain neoplasms or abscesses. Making the distinction between demyelination and infection/malignancies early is important to prevent unnecessary surgical procedures and toxic therapies like radiation and chemotherapy (McAdam *et al.,* 2002). MRI studies demonstrate 1 or 2 large confluent lesions in the deep white matter, usually the centrum semiovale **(Figure 8 a-f).** Lesions are at least 2 cm in size in 2 of 3 dimensions. No additional lesions should be observed on imaging of the brain or spinal cord- this would suggest MS or ADEM. On T1WI, tumefactive demyelination lesions reveal a hypo-intense central area with a thick surrounding band of moderately increased intensity. Lesions are centrally hyper-intense on T2WI. Enhancement, when present, is incomplete. The lesions are characterized by enhancement limited to one side of the lesion; usually the rim facing the lateral ventricles (McAdam *et al*., 2007). Demyelination can be distinguished from other ring enhancing lesions (brain abscesses, tumors, parasitic infections) by the presence of other demyelinating plaques

one or two roughly symmetrical large plaques (greater than 2 cm diameter)

Characteristics of NMO that help to distinguish it from classical MS include:

predominance (Mandler *et al*., 1993; O Riordan *et al*., 1996)

**7. Schilder's disease/myelinoclastic diffuse sclerosis**

Bilateral symmetrical optic neuritis

children (peak age 5-14 years) (Afifi *et al*., 1994). The Poser criteria (1992) for diagnosis are:

lesions

sclerosis

**7.1 Clinical presentation**

**7.2 Neuro-imaging**

signs of raised intra-cranial pressure.

elsewhere in the central nervous system.

Fig. 8. A & B – T2 axial MRI demonstrating multiple well-defined hyper-intense white matter foci surrounded by more ill-defined areas of increased white matter signal intensity consistent with Schilder's Disease. C- Flair axial MRI demonstrating multiple hyper-intense lesions of varying sizes within the white matter with some areas of suppression within the plaques consistent with Schilder's Disease. D- Flair parasagittal MRI demonstrating large flame- shaped white matter plaque with some areas of suppression within the lesions consistent with Schilder's Disease. E & F- T1 with contrast axial MRI demonstrating multiple non- enhancing hypo-intense lesions of varying shapes and sizes within the white matter.

Other supportive diagnostic tests include an elevated CSF protein and an elevation of CSF IgG in 50-60% of patients with Schilder's Disease. Many patients with a large ring enhancing lesion will have a brain biopsy mainly to exclude other disorders.

#### **7.3 Treatment**

The treatment of choice is high dose intravenous corticosteroids. A rapid clinical and radiological response to high dose corticosteroids favors the diagnosis of demyelination.

Acquired Demyelinating Disorders of the CNS in Children 77

multiple sclerosis is a second-stage, chronic, progressive form of the disease where there are no periods of remission, only breaks in attack duration with no recovery from symptoms. Relapsing progressive: have a steady neurologic decline but also suffer clear superimposed

An acute/ Malignant MS (Marburg variant) form presenting with a fulminant, rapidly fatal

Children present with a wide variety of clinical symptomatology including motor, sensory, visual, cerebellar and brainstem dysfunction (Shaw and Alvord., 1987; Sindern *et al*., 1992; Ghezzi *et al*., 1997; Dale *et al*., 2000; Boiko *et al.,* 2002; Pohl *et al*., 2006; Govender *et al*., 2010). Motor manifestations are described as the most common clinical presentation (Duquette *et al*., 1987; Sindern *et al*., 1992; Pohl *et al*., 2006). Polysymptomatic presentation is reported to be more frequent in childhood onset MS compared to adults (Ghezzi *et al*., 1997; Dale *et al*., 2000; Boiko *et al*., 2002). However monosymptomatic presentation is also reported in children (Duquette *et al*., 1987). Encephalopathy and seizures also occur in MS (Gusev *et al*., 2002). Eye involvement is described in up to 50 % of children with MS (Pohl *et al.,* 2006).Optic neuritis in MS is more likely to be unilateral (Dale *et al*., 2000). Optic tract involvement may be asymptomatic and diagnosed only by abnormal visual evoked potentials (Pohl *et al*., 2006). Fatigue in children is more frequent compared to adults with MS (Gusev *et al.,* 2002). Cognitive decline is reported in 30-

Diagnostic evaluation is to exclude other conditions affecting predominantly the white matter and to look for supportive evidence for MS. The workup should also include CSF studies (including cell count, total protein, IgG index, evidence of oligoclonal bands, and cytology) (Hahn *et al*., 2007). CSF Oligoclonal bands are reported in 72-84% of children with MS (Sindern *et al*., 1992; Dale *et al.,* 2000). Oligoclonal bands may be absent initially and only develop during the course of the illness. Leucocytosis in the peripheral blood, though described in MS (Dale *et al*., 2000; Govender *et al.,* 2010), is uncommon and non-specific. Neuro-physiological testing such as visual and auditory evoked potentials are also of

Lesions of MS are typically multiple, discrete, plaque-like and involve predominantly the white matter (Mikaeloff *et al*., 2004). Commonly involved areas in MS include the corpus callosum, periventricular and sub-cortical white matter **(Fig 9a-g)**. Lesions of MS are typically iso- or hypo-intense on T1WI, and hyper-intense on T2W1 and FLAIR sequences. Enhancement of active lesions post-gadolinium may be solid, ring-like or arc-like **(Fig 10a-c).** Children tend to have fewer lesions and less enhancement (Banwell et al., 2007b). However, some children lack typical MRI findings of MS and have either large tumefactive lesions with peri-lesional oedema (Hahn et al., 2004) or deep grey matter involvement. Basal ganglia affectation in MS, though described, is uncommon **(Figure 11 a,b).** Younger children with MS may also have more diffuse, bilateral ill defined lesions (Mikaeloff *et al*., 2004). The International Pediatric MS Study Group strongly recommended additional imaging of the entire spinal cord to identify other sites of demyelination (**Figure 12 a,b).** The cervical spinal

66% of children with MS (Banwell and Anderson 2005; Banwell *et al*., 2007a).

diagnostic importance in detecting sub-clinical evidence of demyelination.

cord is the commonest region involved in MS.

attacks. This is the least common of all subtypes.

disease has also been described.

**8.4 Clinical presentation**

**8.5 Laboratory evaluation**

**8.6 Imaging**

#### **8. Multiple Sclerosis (MS)**

MS is defined in Table 1 (Krupp *et al*., 2007). MS in children is likely an under-recognized phenomenon that poses a unique set of challenges in terms of diagnosis and management. Early accurate diagnosis of MS is vital to facilitate early institution of disease modifying agents.

#### **8.1 Epidemiology**

Childhood onset MS is an uncommon entity however, an estimated 2- 5% of patients with MS have onset of symptoms of MS before 16 years of age (Duquette *et al*., 1987; Boiko *et al*., 2002). The youngest reported patient with MS presented at 10 months of age. This was an indigenous African child who died at 6 years of age after 11 episodes of relapsing neurological symptoms (Shaw and Alvord, 1987). Similar to adult studies, a female preponderance is reported for MS in adolescence (Duquette *et al*., 1987; Govender *et al.,* 2010). However there is no gender predilection in children presenting with MS under 6 years of age (Banwell *et al.,* 2007).

A crude period prevalence for patients of European ancestry was 25.63 per 100 000 and for patients of indigenous African descent was 0.22 per 100 000 (Bhigjee *et a*l., 2007). Adult studies have described a more severe clinical and radiological phenotype in patients of African indigenous ancestry compared to patients of European ancestry (Kaufmann *et al*., 2003; Bhigjee *et al.,* 2007). A retrospective single centre analysis showed a significantly higher relapse-rate in African-American children, compared with whites, suggesting a more aggressive disease course in the former group (Boster *et al*., 2009).

#### **8.2 Pathogenesis**

Genetic and environmental factors are implicated in the aetiology of MS. Twin studies show a 20-30% higher risk of disease in monozygotic twins compared to dizygotic twins. Allelic variation in the MHC class II region exerts the single strongest effect on genetic risk (Ramgopalan SV *et al.,* 2009). The HLA DR1B is the gene marker associated with higher risk of MS (Ness *et al*., 2007). Alleles of IL2RA, IL7RA (Hafler et al., 2007), the ecotropic viral integration site 5 (*EVI5*) (Hoppenbrouwers *et al*., 2008) and kinesin family member 1B (*KIF1B*) genes (Aulchenko *et al.,* 2008) have recently been shown to increase susceptibility to MS.

Epidemiological studies implicate environmental factors such as geographical variations (Kurtzke and Hyllested, 1979), season of birth (Sadovnick *et al.,* 2007) and migration patterns (Pugliatti *et al*., 2006) in the aetiology of MS. Emerging evidence supports sunlight or vitamin D as an important environmental factor in aetiology (Ramgopalan SV *et al*., 2009). Children exposed to parental smoking also have a higher risk of MS (Mikaeloff *et al*., 2007).

#### **8.3 Sub-types of MS**

The National MS Society in the US in 1996 categorized MS into four internationally recognized forms (Lublin and Reingold, 1996).

Relapsing-remitting: refers to MS that has exacerbations/relapses followed by symptom-free periods of remission. This is the commonest form of MS in children (Ruggierri *et al*., 2004).

Primary Progressive: It is characterized by gradual clinical decline from the time of disease onset with no distinct periods of remission or relapses. There maybe plateau periods during the disease but no periods of being symptom free. This entity, though rare in children, is reported (Duquette *et al.*, 1987; Govender *et al*., 2010).

Secondary Progressive: This type begins with a relapsing remitting course which may last several years before the onset of the secondary progressive stage. Secondary progressive multiple sclerosis is a second-stage, chronic, progressive form of the disease where there are no periods of remission, only breaks in attack duration with no recovery from symptoms.

Relapsing progressive: have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes.

An acute/ Malignant MS (Marburg variant) form presenting with a fulminant, rapidly fatal disease has also been described.

#### **8.4 Clinical presentation**

76 Neuroimaging – Clinical Applications

MS is defined in Table 1 (Krupp *et al*., 2007). MS in children is likely an under-recognized phenomenon that poses a unique set of challenges in terms of diagnosis and management. Early accurate diagnosis of MS is vital to facilitate early institution of disease modifying agents.

Childhood onset MS is an uncommon entity however, an estimated 2- 5% of patients with MS have onset of symptoms of MS before 16 years of age (Duquette *et al*., 1987; Boiko *et al*., 2002). The youngest reported patient with MS presented at 10 months of age. This was an indigenous African child who died at 6 years of age after 11 episodes of relapsing neurological symptoms (Shaw and Alvord, 1987). Similar to adult studies, a female preponderance is reported for MS in adolescence (Duquette *et al*., 1987; Govender *et al.,* 2010). However there is no gender predilection in children presenting with MS under 6

A crude period prevalence for patients of European ancestry was 25.63 per 100 000 and for patients of indigenous African descent was 0.22 per 100 000 (Bhigjee *et a*l., 2007). Adult studies have described a more severe clinical and radiological phenotype in patients of African indigenous ancestry compared to patients of European ancestry (Kaufmann *et al*., 2003; Bhigjee *et al.,* 2007). A retrospective single centre analysis showed a significantly higher relapse-rate in African-American children, compared with whites, suggesting a more

Genetic and environmental factors are implicated in the aetiology of MS. Twin studies show a 20-30% higher risk of disease in monozygotic twins compared to dizygotic twins. Allelic variation in the MHC class II region exerts the single strongest effect on genetic risk (Ramgopalan SV *et al.,* 2009). The HLA DR1B is the gene marker associated with higher risk of MS (Ness *et al*., 2007). Alleles of IL2RA, IL7RA (Hafler et al., 2007), the ecotropic viral integration site 5 (*EVI5*) (Hoppenbrouwers *et al*., 2008) and kinesin family member 1B (*KIF1B*) genes (Aulchenko *et al.,* 2008) have recently been shown to increase susceptibility to MS. Epidemiological studies implicate environmental factors such as geographical variations (Kurtzke and Hyllested, 1979), season of birth (Sadovnick *et al.,* 2007) and migration patterns (Pugliatti *et al*., 2006) in the aetiology of MS. Emerging evidence supports sunlight or vitamin D as an important environmental factor in aetiology (Ramgopalan SV *et al*., 2009). Children exposed to parental smoking also have a higher risk of MS (Mikaeloff *et al*., 2007).

The National MS Society in the US in 1996 categorized MS into four internationally

Relapsing-remitting: refers to MS that has exacerbations/relapses followed by symptom-free periods of remission. This is the commonest form of MS in children (Ruggierri *et al*., 2004). Primary Progressive: It is characterized by gradual clinical decline from the time of disease onset with no distinct periods of remission or relapses. There maybe plateau periods during the disease but no periods of being symptom free. This entity, though rare in children, is

Secondary Progressive: This type begins with a relapsing remitting course which may last several years before the onset of the secondary progressive stage. Secondary progressive

aggressive disease course in the former group (Boster *et al*., 2009).

**8. Multiple Sclerosis (MS)**

years of age (Banwell *et al.,* 2007).

**8.1 Epidemiology**

**8.2 Pathogenesis**

**8.3 Sub-types of MS**

recognized forms (Lublin and Reingold, 1996).

reported (Duquette *et al.*, 1987; Govender *et al*., 2010).

Children present with a wide variety of clinical symptomatology including motor, sensory, visual, cerebellar and brainstem dysfunction (Shaw and Alvord., 1987; Sindern *et al*., 1992; Ghezzi *et al*., 1997; Dale *et al*., 2000; Boiko *et al.,* 2002; Pohl *et al*., 2006; Govender *et al*., 2010). Motor manifestations are described as the most common clinical presentation (Duquette *et al*., 1987; Sindern *et al*., 1992; Pohl *et al*., 2006). Polysymptomatic presentation is reported to be more frequent in childhood onset MS compared to adults (Ghezzi *et al*., 1997; Dale *et al*., 2000; Boiko *et al*., 2002). However monosymptomatic presentation is also reported in children (Duquette *et al*., 1987). Encephalopathy and seizures also occur in MS (Gusev *et al*., 2002). Eye involvement is described in up to 50 % of children with MS (Pohl *et al.,* 2006).Optic neuritis in MS is more likely to be unilateral (Dale *et al*., 2000). Optic tract involvement may be asymptomatic and diagnosed only by abnormal visual evoked potentials (Pohl *et al*., 2006). Fatigue in children is more frequent compared to adults with MS (Gusev *et al.,* 2002). Cognitive decline is reported in 30- 66% of children with MS (Banwell and Anderson 2005; Banwell *et al*., 2007a).

#### **8.5 Laboratory evaluation**

Diagnostic evaluation is to exclude other conditions affecting predominantly the white matter and to look for supportive evidence for MS. The workup should also include CSF studies (including cell count, total protein, IgG index, evidence of oligoclonal bands, and cytology) (Hahn *et al*., 2007). CSF Oligoclonal bands are reported in 72-84% of children with MS (Sindern *et al*., 1992; Dale *et al.,* 2000). Oligoclonal bands may be absent initially and only develop during the course of the illness. Leucocytosis in the peripheral blood, though described in MS (Dale *et al*., 2000; Govender *et al.,* 2010), is uncommon and non-specific. Neuro-physiological testing such as visual and auditory evoked potentials are also of diagnostic importance in detecting sub-clinical evidence of demyelination.

#### **8.6 Imaging**

Lesions of MS are typically multiple, discrete, plaque-like and involve predominantly the white matter (Mikaeloff *et al*., 2004). Commonly involved areas in MS include the corpus callosum, periventricular and sub-cortical white matter **(Fig 9a-g)**. Lesions of MS are typically iso- or hypo-intense on T1WI, and hyper-intense on T2W1 and FLAIR sequences. Enhancement of active lesions post-gadolinium may be solid, ring-like or arc-like **(Fig 10a-c).** Children tend to have fewer lesions and less enhancement (Banwell et al., 2007b). However, some children lack typical MRI findings of MS and have either large tumefactive lesions with peri-lesional oedema (Hahn et al., 2004) or deep grey matter involvement. Basal ganglia affectation in MS, though described, is uncommon **(Figure 11 a,b).** Younger children with MS may also have more diffuse, bilateral ill defined lesions (Mikaeloff *et al*., 2004). The International Pediatric MS Study Group strongly recommended additional imaging of the entire spinal cord to identify other sites of demyelination (**Figure 12 a,b).** The cervical spinal cord is the commonest region involved in MS.

Acquired Demyelinating Disorders of the CNS in Children 79

A B C

A B

demyelination in a patient with MS.

white matter areas (Tintore *et al.,* 2000).

Fig. 10. A- T1 with contrast parasagittal MRI of brain demonstrating rim-enhancing plaquelike lesion typical of active demyelination in a patient with MS. B- T1 with contrast axial MRI demonstrating ring enhancement of left brachium pontis lesion consistent with active demyelination in a patient with MS. C- T1 with contrast axial MRI demonstrating ill-defined irregular marginal enhancement of the plaque-like lesions consistent with active

Fig. 11. A- Flair axial MRI of brain demonstrating 2 lesions in the right basal ganglia. This is unusual for MS. B- Flair axial MRI demonstrating multiple hyper-intense lesions in the periventricular white matter as well as left basal ganglia(atypical) consistent with MS.

MRS reveals a reduction in NAA and an elevation in choline, lipids and lactate in active lesions (Smith AB, 2009). Volumetric MRI studies reveal progressive loss of tissue in white matter tracts early in the course of the disease (Miller *et al*., 2002). A single study of Magnetization transfer imaging and Diffusion tensor imaging in children with MS suggested that there was no evidence of white matter degeneration in normal appearing

Fig. 9. A- T2 parasagittal MRI of the brain demonstrating flame-shaped hyper-intense lesion perpendicular to lateral ventricle consistent with MS. B- Flair axial MRI demonstrating multiple asymmetrical hyper-intense plaque-like lesions in the centrum-semiovale.  G-Flair axial MRI demonstrating rounded hyper-intense lesion in left brachium pontis consistent with demyelination.

A B

C D

E F G

demonstrating asymmetrical hyper-intense white matter lesions consistent with

hyper-intense lesion in left brachium pontis consistent with demyelination.

demyelination and MS. E- Flair axial of brain demonstrating hyper-intense right parietal white matter plaque-like lesion and left subtle white matter hyperintensity consistent with MS. F- Flair axial of brainstem demonstrating pontine and brachium pontis high signal intensity lesions consistent with demyelination. G-Flair axial MRI demonstrating rounded

Fig. 9. A- T2 parasagittal MRI of the brain demonstrating flame-shaped hyper-intense lesion perpendicular to lateral ventricle consistent with MS. B- Flair axial MRI demonstrating multiple asymmetrical hyper-intense plaque-like lesions in the centrum-semiovale. Features are consistent with MS. C -Flair axial MRI of brain demonstrating 2 periventricular hyperintense white matter lesions consistent with MS. D- Flair axial at level of lateral ventricles

Fig. 10. A- T1 with contrast parasagittal MRI of brain demonstrating rim-enhancing plaquelike lesion typical of active demyelination in a patient with MS. B- T1 with contrast axial MRI demonstrating ring enhancement of left brachium pontis lesion consistent with active demyelination in a patient with MS. C- T1 with contrast axial MRI demonstrating ill-defined irregular marginal enhancement of the plaque-like lesions consistent with active demyelination in a patient with MS.

Fig. 11. A- Flair axial MRI of brain demonstrating 2 lesions in the right basal ganglia. This is unusual for MS. B- Flair axial MRI demonstrating multiple hyper-intense lesions in the periventricular white matter as well as left basal ganglia(atypical) consistent with MS.

MRS reveals a reduction in NAA and an elevation in choline, lipids and lactate in active lesions (Smith AB, 2009). Volumetric MRI studies reveal progressive loss of tissue in white matter tracts early in the course of the disease (Miller *et al*., 2002). A single study of Magnetization transfer imaging and Diffusion tensor imaging in children with MS suggested that there was no evidence of white matter degeneration in normal appearing white matter areas (Tintore *et al.,* 2000).

Acquired Demyelinating Disorders of the CNS in Children 81

24 Interferon beta 1a Reduction in

relapse rate

relapse rate

relapse-2/7 Stable EDSS- 3/7

remission in all

relapse rate Stabilization of

EDSS

score

Reduction in \*EDSS

Study No. of patients Treatment Outcomes

Tenembaum and Segura, 2006

**8.8 Prognosis**

*al*., 2006).

\* EDSS: Extended Disability Status Scale

**9. Clinically isolated syndromes**

Table 2. Studies of specific treatment interventions in MS

Ghezzi *et al*, 2007 52 Interferon beta 1a Reduction in

Kornek *et al,* 2003 7 Glatimer Acetate Reduction in

Huppke *et al,* 2008 3 Natalizumab Induction of

Makhani *et al,* 2009 17 Cyclophosphamide Reduction in

Most children with MS follow a relapsing, remitting course with increasing neurodisability (Boiko *et al.,* 2002). A slower rate of progression of disease compared to adults suggests more plasticity and potential for recovery in the developing CNS (Simone *et al.,* 2002). Children tend to have more relapses in the first 2 years of the disease (Simone *et al*., 2002; Mikaeloff *et al.,* 2006). Patients with childhood-onset MS also take longer to reach the stage of severe disability but reach irreversible neurological disability at a younger age compared to patients with adult onset disease (Renoux *et al.,* 2007). More severe disease was noted in girls; when the time between the first and second attacks was <1 year; for childhood-onset multiple sclerosis fulfilling MRI diagnostic criteria at onset; for an absence of severe mental state changes at onset; and for a progressive course (Mikaeloff *et*

These episodes may be mono-focal (the clinical features can be attributed to a single CNS site) or multi-focal if the clinical features can not be explained by a single lesion. These include isolated optic neuritis, transverse myelitis, brainstem **(Fig 13 a-d)** or cortical lesions. Typically in contrast to ADEM there is no associated fever or encephalopathy. A CIS often poses a diagnostic and therapeutic challenge. Multiple lesions (> 4 lesions) (Morissey *et al*., 1993) on the MRI increase the risk of evolution to MS. In adult studies up to 80% of patients with a CIS evolve MS (Brex *et al*., 2002). Brainstem lesions in CIS are associated with a worse prognosis (Tintore *et al*., 2010). Children with CIS tend to have more infra-tentorial lesions

Fig. 12. A- T2 sagittal MRI of cervical spine in a patient with MS demonstrating an ill-defined expansile hyper-intense lesion in the proximal cord consistent with demyelination. B- T1 with contrast sagittal MRI of cervical spine in a patient with MS demonstrating ill-defined contrast enhancement of the lesion in 12A consistent with active demyelination.

#### **8.7 Treatment**

MS is a chronic condition with significant impact on all aspects of the family's life. Management should be trans-disciplinary involving psychologists, physiotherapists, occupational therapists and school teachers.

#### **8.7.1 Management of relapses**

The mainstay of managing relapses is high dose corticosteroids. High dose IV corticosteroids (10-30mg/kg/day) for 3-5 days, is usually used with an optional oral tapering dose. High dose oral steroids were found to be efficacious in adults (Morrow *et al.,* 2004). Plasmapharesis and IVIG are alternatives to be considered if steroids are not effective (Hahn *et al*., 1996; Duzova and Bakkaloglu, 2008).

#### **8.7.2 Disease modifying therapy**

These therapies are known to alter the disease course and outcomes. They reduce the frequency and severity of relapses (Mikaeloff *et al.,* 2001; Kornek *et al*., 2003; Tenembaum and Segura, 2006;). Patients on therapy are shown to have better outcomes compared to untreated patients (Mikaeloff *et al*., 2008). First line agents include Interferon beta 1a, 1b and Glatimer acetate. Case reports of second line therapies used include Natalizumab, Cyclophosphamide and Mitoxantrone.

\* EDSS: Extended Disability Status Scale

Table 2. Studies of specific treatment interventions in MS

#### **8.8 Prognosis**

80 Neuroimaging – Clinical Applications

A B

Fig. 12. A- T2 sagittal MRI of cervical spine in a patient with MS demonstrating an ill-defined expansile hyper-intense lesion in the proximal cord consistent with demyelination. B- T1 with contrast sagittal MRI of cervical spine in a patient with MS demonstrating ill-defined

MS is a chronic condition with significant impact on all aspects of the family's life. Management should be trans-disciplinary involving psychologists, physiotherapists,

The mainstay of managing relapses is high dose corticosteroids. High dose IV corticosteroids (10-30mg/kg/day) for 3-5 days, is usually used with an optional oral tapering dose. High dose oral steroids were found to be efficacious in adults (Morrow *et al.,* 2004). Plasmapharesis and IVIG are alternatives to be considered if steroids are not effective

These therapies are known to alter the disease course and outcomes. They reduce the frequency and severity of relapses (Mikaeloff *et al.,* 2001; Kornek *et al*., 2003; Tenembaum and Segura, 2006;). Patients on therapy are shown to have better outcomes compared to untreated patients (Mikaeloff *et al*., 2008). First line agents include Interferon beta 1a, 1b and Glatimer acetate. Case reports of second line therapies used include Natalizumab,

contrast enhancement of the lesion in 12A consistent with active demyelination.

**8.7 Treatment**

occupational therapists and school teachers.

(Hahn *et al*., 1996; Duzova and Bakkaloglu, 2008).

**8.7.1 Management of relapses**

**8.7.2 Disease modifying therapy**

Cyclophosphamide and Mitoxantrone.

Most children with MS follow a relapsing, remitting course with increasing neurodisability (Boiko *et al.,* 2002). A slower rate of progression of disease compared to adults suggests more plasticity and potential for recovery in the developing CNS (Simone *et al.,* 2002). Children tend to have more relapses in the first 2 years of the disease (Simone *et al*., 2002; Mikaeloff *et al.,* 2006). Patients with childhood-onset MS also take longer to reach the stage of severe disability but reach irreversible neurological disability at a younger age compared to patients with adult onset disease (Renoux *et al.,* 2007). More severe disease was noted in girls; when the time between the first and second attacks was <1 year; for childhood-onset multiple sclerosis fulfilling MRI diagnostic criteria at onset; for an absence of severe mental state changes at onset; and for a progressive course (Mikaeloff *et al*., 2006).

#### **9. Clinically isolated syndromes**

These episodes may be mono-focal (the clinical features can be attributed to a single CNS site) or multi-focal if the clinical features can not be explained by a single lesion. These include isolated optic neuritis, transverse myelitis, brainstem **(Fig 13 a-d)** or cortical lesions. Typically in contrast to ADEM there is no associated fever or encephalopathy. A CIS often poses a diagnostic and therapeutic challenge. Multiple lesions (> 4 lesions) (Morissey *et al*., 1993) on the MRI increase the risk of evolution to MS. In adult studies up to 80% of patients with a CIS evolve MS (Brex *et al*., 2002). Brainstem lesions in CIS are associated with a worse prognosis (Tintore *et al*., 2010).  Markers comparing ADEM to a first episode of MS

Deep Grey matter involvement

No neuro deficit after 1st

focal signs

Clinical Presentation

Laboratory features

MRI

Characteristics

Fig. 13. (B&C same patient) Clinically Isolated Syndrome. A- T2 axial MRI demonstrating abnormal increased signal in the brainstem which was the only abnormal lesion. Clinically this patient had a CIS.  Features consistent with a unilateral Optic Neuritis. Remainder of brain and spine were normal.  Features consistent with a unilateral Optic Neuritis. Remainder of brain and spine were normal.  Features consistent with Optic Neuritis (worse on the right). Remainder of brain and spine were normal.

A B

C D

Neuritis (worse on the right). Remainder of brain and spine were normal.

Fig. 13. (B&C same patient) Clinically Isolated Syndrome. A- T2 axial MRI demonstrating abnormal increased signal in the brainstem which was the only abnormal lesion. Clinically this patient had a CIS.  Features consistent with a unilateral Optic Neuritis. Remainder of brain and spine were normal.  Features consistent with a unilateral Optic Neuritis. Remainder of brain and spine were normal.  Features consistent with Optic

Table 3. Markers comparing ADEM to a first episode of MS

Acquired Demyelinating Disorders of the CNS in Children 85

disease

**Nutritional Deficiencies**

**Osmotic Demyelination Syndrome**

**Mitochondrial** Leigh's Disease Neuro-regression with

Vitamin B12 deficiency

Lead, Isoniazid **Infiltrative** Sarcoidosis Cranial neuropathies,

Vitamin E, Folate deficiency

**Toxins/ Drugs** Radiation History of exposure -Diffuse, bilateral

Metachromic Leukodystrophy, Krabbe's Disease, Alexander's

dystonia/opthalmoplegia Hyperlactataemia

Anaemia, peripheral neuropathy, Myelopathy

aseptic meningitis, visual

hypothalamic dysfunction

Rapid correction of Hypoor hypernatraemia

disturbances

Histiocytosis Visual disturbances,

Table 4. Main differential diagnosis of acquired white matter diseases on MRI

periventricular and

central WM involved -T1WI ↓, T2WI↑ -Sparing of subcortical U Fibres

lesions -May have hypothalamic and

T2WI↑

lesions

WM -T1WI↓

meningeal enhancement

↑T2WI

Developmental delay, pyramidal tract signs,

Immunocompromised -Multi-focal ↑T2 WI

lesions

frequently -MRS may help

involved -Leading edge enhancement in peri-trigonal

area

microcephaly

Multi-system autoimmune disorder Anti-nuclear factor

Isolated CNS angiitis, CADASIL (adult disorder-rare in children)

cytospin –malignant cells

hyperpigmentation of skin, behaviour and learning problems,

Abnormal very long chain

positive

Boys with

fatty acids

Disorder Example Clinical/ Laboratory Radiological

Encephalopathy

Progressive Multi-

Leucoencephalopa thy (JC Virus)

Systemic Lupus Erythematosus

**Tumor** CNS Lymphoma Insiduous onset, CSF

**Leukodystrophies** Adrenoleukody-

strophy

Medulloblastoma, Astrocytoma

**Other infections** Sub-acute Sclerosing Panencephalitis, Lymes Disease, Neurosyphillus, HTLV1, Borreliosis

focal

**Infections** HIV

**Auto-**

**immune/Vasculitides**

Table 4. Main differential diagnosis of acquired white matter diseases on MRI

Acquired Demyelinating Disorders of the CNS in Children 87

A B

C D

E F G

contrast enhancement. Features consistent with Pontine Myelinolysis.

bilaterally. This patient has features of HIV encephalopathy. C- Flair axial MRI

Fig. 14. A & B- T2 axial MRI demonstrating diffuse brain shrinkage/atrophy with ex-vacuo dilatation of the ventricles and abnormal increased signal intensity in the deep white matter

demonstrating bilateral symmetrical increased signal intensity in the frontal white matter. This patient was diagnosed with PML. D- T2 axial MRI demonstrating bilateral symmetrical confluent abnormal increased white matter signal intensity in the posterior white matter consistent with Adrenoleukodystrophy. E- T1 with contrast axial MRI of same patient as 14D demonstrating peripheral enhancement of the white matter lesions. F- T2 axial MRI demonstrating well-defined rounded hyper-intense lesion in the pons. Note peripheral sparing of the pons. (Compared to figure 14G). Features consistent with Osmotic/ Pontine Myelinolysis. G- T1 with contrast sagittal MRI of the same pontine lesion as 14F showing no

(Ghassemi *et al.,* 2008). This may be related to the differences in myelination patterns and maturation in children compared to adults. A radiologically isolated syndrome (RIS) is defined by incidental MRI findings suggestive of MS in an asymptomatic patient lacking any history, symptoms, or signs of MS (Okuda *et al.,* 2009).

#### **10. Risk of recurrence after a first demyelinating event**

Predicting the risk of a first episode of demyelination evolving on to MS is important as new immunomodulating therapies become available. Early initiation of disease modifying therapy reduces the risk of relapse and long-term disability (Jacobs *et al.,* 2000). Patients with "ADEM" progressing to MS vary from 0-29% (Belman *et al*., 2007). Multiple historical, clinical, laboratory and radiological criteria are used to predict the risk of recurrence/ progression to MS (Table 3).

A seasonal pattern, a history of a precipitant, seizures, bilateral optic neuritis and encephalopathy are considered more likely in ADEM compared to MS (Dale *et al.,* 2005). Inflammatory markers, a high cerebrospinal fluid protein and leucocytosis are also more common in ADEM (Kesselring *et al.,* 1990). MRI characteristics that are predictive of evolution to MS include well defined lesions that are peri-aqueductal or perpendicular to the corpus callosum (Dale *et al.,* 2000), deep grey matter involvement and lesions that enhance post contrast (Govender *et al.,* 2010).

#### **11. Differential diagnosis of white matter disease in children**

The differential diagnosis for a child who presents with a neurological symptom and white matter lesions on neuro-imaging is vast and includes infectious diseases, leukodystrophies, tumors, vasculitides, toxins and vitamin deficiencies. In resource poor countries, CNS infections must be excluded first as they are common and have acute therapeutic implications.

**CNS infections** must be excluded in children presenting acutely especially with fever and encephalopathy. CNS infections that may present with multifocal white matter lesions include HTLV-1, Borreliosis and Subacute Sclerosing Panencephalitis. In resource poor settings HIV Encephalopathy **(Figure 14 a,b)** is common and is also characterized by confluent white matter lesions. Progressive Multi-focal Leukoencephalopathy **(Figure 14 c),**  is also common in immuno-compromised patients.

Neurometabolic disorders, such as Adrenoleukodystrophy **(Figure 14 d,e),** presents with primary white matter disease.

**Osmotic Myelinolysis (Figure 14 f,g)** is thought to be related to osmotic shifts associated with rapid correction of fluid and electrolyte abnormalities (especially sodium abnormalities). Malnourished children are at greater risk for developing myelinolysis. Lesions typically occur in the pons but have also been reported in extra-pontine sites such as the basal ganglia, cerebral cortex and cerebellar peduncles.

**Nutritional deficiencies** such as vitamins B12, E and folate deficiencies may also cause white matter lesions.

**Drugs and toxins** implicated in demyelination include tin, lead, isoniazid and radiation.

**Collagen Vascular Disease**s refer to a group of auto-immune mediated disorders. The neurological manifestations are diverse. Neuro-imaging may show multi-focal white matter lesions- involving the cortex, cerebellum or spinal cord.

(Ghassemi *et al.,* 2008). This may be related to the differences in myelination patterns and maturation in children compared to adults. A radiologically isolated syndrome (RIS) is defined by incidental MRI findings suggestive of MS in an asymptomatic patient lacking

Predicting the risk of a first episode of demyelination evolving on to MS is important as new immunomodulating therapies become available. Early initiation of disease modifying therapy reduces the risk of relapse and long-term disability (Jacobs *et al.,* 2000). Patients with "ADEM" progressing to MS vary from 0-29% (Belman *et al*., 2007). Multiple historical, clinical, laboratory and radiological criteria are used to predict the risk of recurrence/

A seasonal pattern, a history of a precipitant, seizures, bilateral optic neuritis and encephalopathy are considered more likely in ADEM compared to MS (Dale *et al.,* 2005). Inflammatory markers, a high cerebrospinal fluid protein and leucocytosis are also more common in ADEM (Kesselring *et al.,* 1990). MRI characteristics that are predictive of evolution to MS include well defined lesions that are peri-aqueductal or perpendicular to the corpus callosum (Dale *et al.,* 2000), deep grey matter involvement and lesions that

The differential diagnosis for a child who presents with a neurological symptom and white matter lesions on neuro-imaging is vast and includes infectious diseases, leukodystrophies, tumors, vasculitides, toxins and vitamin deficiencies. In resource poor countries, CNS infections must be excluded first as they are common and have acute therapeutic

**CNS infections** must be excluded in children presenting acutely especially with fever and encephalopathy. CNS infections that may present with multifocal white matter lesions include HTLV-1, Borreliosis and Subacute Sclerosing Panencephalitis. In resource poor settings HIV Encephalopathy **(Figure 14 a,b)** is common and is also characterized by confluent white matter lesions. Progressive Multi-focal Leukoencephalopathy **(Figure 14 c),**

Neurometabolic disorders, such as Adrenoleukodystrophy **(Figure 14 d,e),** presents with

**Osmotic Myelinolysis (Figure 14 f,g)** is thought to be related to osmotic shifts associated with rapid correction of fluid and electrolyte abnormalities (especially sodium abnormalities). Malnourished children are at greater risk for developing myelinolysis. Lesions typically occur in the pons but have also been reported in extra-pontine sites such as

**Nutritional deficiencies** such as vitamins B12, E and folate deficiencies may also cause

**Drugs and toxins** implicated in demyelination include tin, lead, isoniazid and radiation. **Collagen Vascular Disease**s refer to a group of auto-immune mediated disorders. The neurological manifestations are diverse. Neuro-imaging may show multi-focal white matter

any history, symptoms, or signs of MS (Okuda *et al.,* 2009).

progression to MS (Table 3).

implications.

enhance post contrast (Govender *et al.,* 2010).

is also common in immuno-compromised patients.

the basal ganglia, cerebral cortex and cerebellar peduncles.

lesions- involving the cortex, cerebellum or spinal cord.

primary white matter disease.

white matter lesions.

**10. Risk of recurrence after a first demyelinating event**

**11. Differential diagnosis of white matter disease in children**

Fig. 14. A & B- T2 axial MRI demonstrating diffuse brain shrinkage/atrophy with ex-vacuo dilatation of the ventricles and abnormal increased signal intensity in the deep white matter bilaterally. This patient has features of HIV encephalopathy. C- Flair axial MRI demonstrating bilateral symmetrical increased signal intensity in the frontal white matter. This patient was diagnosed with PML. D- T2 axial MRI demonstrating bilateral symmetrical confluent abnormal increased white matter signal intensity in the posterior white matter consistent with Adrenoleukodystrophy. E- T1 with contrast axial MRI of same patient as 14D demonstrating peripheral enhancement of the white matter lesions. F- T2 axial MRI demonstrating well-defined rounded hyper-intense lesion in the pons. Note peripheral sparing of the pons. (Compared to figure 14G). Features consistent with Osmotic/ Pontine Myelinolysis. G- T1 with contrast sagittal MRI of the same pontine lesion as 14F showing no contrast enhancement. Features consistent with Pontine Myelinolysis.

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**4**

*Venezuela*

**Landau Kleffner Syndrome:**

José Guevara Campos1 and Lucía González Guevara2

The first recording of electromagnetic fields in the brain, or magnetoencephalography (MEG), were performed in 1968 at the Massachussets Institute of Techonology in Boston, by the David Cohen team, exploring alpha rhythm with the aid of a single sensor machine (Cohen,1968). In 1972 Cohen again studied alpha rhythm in normal subjects, and response to hyperventilation in a patient with partial complex seizures (Cohen, 1972). Until the mideighties, MEG equipment had a single sensor that in practice meant, in addition to spatial limitation of the study, that is was necessary to prolong the studies excessively until it was

Magnetoencefalography, with up to 148 channels, has been more useful in dipole localization and evaluating transcallosal spread than traditional EEG, given the limited channels in the 10-20 system. At present, over hundred MEG installations worldwide contribute to our knowledge about the function and development of the human brain (Pateau, 2002). Most MEG studies have been conducted with adult subjects, but some MEG data already exist on children. Pediatric MEG studies have mainly focused on epilepsy surgery, on the Landau-Kleffner syndrome and related disorders, on sensory cortex

MEG is a noninvasive technique that measure the magnetic fields generated by intracellular current flow in the dendrites of the pyramidal neurons of the brain cortex. The fluctuations of the magnetic field produced by this flow of current can be recorded from the outside of scalp and can subsequently be used to locate the cortical generators of that activity with a temporal resolution measured in millisecond. These characteristic made MEG an invalidly useful tool to study the brain centers of cognitive functions. The way, MEG had served to show that there is a neuronal dynamic neuronal involved in the language process (Pulvermuller,et al.,2003;Wilson,et al.,2005;Pammer,et al.,2004) and that, measuring the magnetic fields derived from that activity helps to locate the sources of electrical activity

Despite being a relatively new technique, MEG is fast becoming an essential tool for clinical physicians, including neurophysiologist, to give an accurate diagnosis Although the main applications of the technique are found in the area of presurgical evaluation, epilepsy and

properties in progressive myoclonus epilepsies, and on dyslexia.

electric in the human brain in a noninvasive manner(Ray & Bowyer,2010).

**1. Introduction**

**1.1 Magnetoencephalography**

possible to gather the required data.

*1Pediatric Service of the Hospital "Felipe Guevara Rojas",*

*2Epilepsy and Electroencephalography Unit, El Tigre*

**Neuroradiology Aspect**

 *Universidad de Oriente, El Tigre,*

### **Landau Kleffner Syndrome: Neuroradiology Aspect**

José Guevara Campos1 and Lucía González Guevara2 *1Pediatric Service of the Hospital "Felipe Guevara Rojas", Universidad de Oriente, El Tigre, 2Epilepsy and Electroencephalography Unit, El Tigre Venezuela*

#### **1. Introduction**

96 Neuroimaging – Clinical Applications

Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG (2006).Revised diagnostic criteria for neuromyelitis optica. *Neurology* 66 (10): 1485–1489. Wingerchuk DM, Weinshenker BG (2005). Neuromyelitis Optica. *Curr Treat Options Neurol*

7(3): 173-82

#### **1.1 Magnetoencephalography**

The first recording of electromagnetic fields in the brain, or magnetoencephalography (MEG), were performed in 1968 at the Massachussets Institute of Techonology in Boston, by the David Cohen team, exploring alpha rhythm with the aid of a single sensor machine (Cohen,1968). In 1972 Cohen again studied alpha rhythm in normal subjects, and response to hyperventilation in a patient with partial complex seizures (Cohen, 1972). Until the mideighties, MEG equipment had a single sensor that in practice meant, in addition to spatial limitation of the study, that is was necessary to prolong the studies excessively until it was possible to gather the required data.

Magnetoencefalography, with up to 148 channels, has been more useful in dipole localization and evaluating transcallosal spread than traditional EEG, given the limited channels in the 10-20 system. At present, over hundred MEG installations worldwide contribute to our knowledge about the function and development of the human brain (Pateau, 2002). Most MEG studies have been conducted with adult subjects, but some MEG data already exist on children. Pediatric MEG studies have mainly focused on epilepsy surgery, on the Landau-Kleffner syndrome and related disorders, on sensory cortex properties in progressive myoclonus epilepsies, and on dyslexia.

MEG is a noninvasive technique that measure the magnetic fields generated by intracellular current flow in the dendrites of the pyramidal neurons of the brain cortex. The fluctuations of the magnetic field produced by this flow of current can be recorded from the outside of scalp and can subsequently be used to locate the cortical generators of that activity with a temporal resolution measured in millisecond. These characteristic made MEG an invalidly useful tool to study the brain centers of cognitive functions. The way, MEG had served to show that there is a neuronal dynamic neuronal involved in the language process (Pulvermuller,et al.,2003;Wilson,et al.,2005;Pammer,et al.,2004) and that, measuring the magnetic fields derived from that activity helps to locate the sources of electrical activity electric in the human brain in a noninvasive manner(Ray & Bowyer,2010).

Despite being a relatively new technique, MEG is fast becoming an essential tool for clinical physicians, including neurophysiologist, to give an accurate diagnosis Although the main applications of the technique are found in the area of presurgical evaluation, epilepsy and

Landau Kleffner Syndrome: Neuroradiology Aspect 99

MEG´s special sensitivity towards the currents discharges in the cerebral sulci and fissures have fostered the study of patients with Landau-Kleffner syndrome, for whom an epileptogenic area is proposed in the persylvian region. In these patients, MEG has had an impotant role for the selection of patients who are candidates to multiple subpial transection

The contribution of MEG to epilepsy surgery does not simple lie in more accurate or exact definition of the epileptogenic area alone, but, in addition, MEG contributes non invasive alternatives to locate eloquent cortex area that must be preserved during a surgical

A moving electric charge is always associated with an electric field and concomitant magnetic field surrounding the axis movement fig 2a. Electroencephalogram (EEG) and MEG signals are belied to reflect synchronous postsynatic currents in thousands of parallel apical dendrites. Despite being ultimately due to the same primary currents, EEG and MEG signals differ at some important points (Paetau, 2002). First, only tangential currents, parallel to the head surface, give rise to an extracranial magnetic field. Because the apical dendrites typically run perpendicular to the cortex surface, MEG signal mainly arise in fissure walls fig2b. The EEG signals, on the other hand, are dominated by radial currents, while the tangential ones may require signal averaging to be detected. The complementary sensitivity to current warrants combined use of EEG and MEG whenever possible. Second, in homogeneous tissue conductivity of the human head tends to spread out the signal, but does not alter the magnetic fields. Therefore, tumors, cysts, calcified lesions and skull defects cause less distortion on MEG than EEG signals (Vander,et al., 1998). Third, signal attenuation in EEG is caused by poorly conducting tissue, while the magnetic field fades off proportionally to the second power of the distance from the source. Infant and persons with small heads should preferably be studies with systems composed of two part-head devices adjustable according to the head size or with specially designed baby devices. Fourth, different practical problems hamper data acquisition. MEG sensors are in a rigid helmet and the head as to be kept immobile with respect to the helmet. Long Term recordings or recordings of major motor seizures area far not possible with MEG, but continuous monitoring of the head position may offer relief to some of the movement problems. Finally, MEG and EEG have partly differing artifact profiles: MEG is less sensitive to muscle artifacts than EEG. On the other hand, magnetic materials moving with respiration (Traces from craniotomy drills, some shunt materials, tooth braces, cochlear implants, etc) may cause

Acquired epileptic regression syndromes are disabling childhood disorder, were a previously healthy child deteriorates over a week to months. The children may or may not show overt seizures, but their EEG usually displays almost continuous epileptiform spike and wave activity, especially during sleep. In acquired epileptic aphasia or the Landau-Kleffner syndrome (Landau, 1957), the regression affects receptive language and /or auditory perception. Epileptiform spike-and wave discharges appear during the first few weeks, and have been proposed to causally related to cognitive disability. Some LKS children develop giant auditory N100m response with similar auditory cortex sources and

treatment (Pateau,et al.,1999).

procedure (Sibasaki,et al., 2007).

**1.2 Basic principles of MEG**

serious artifacts or even destroy the MEG data.

**1.3 MEG in acquired epileptiform regression syndromes**

brain tumors (Frye,et al.,2009), especially in the functional localization of epileptic focus, another condition in for which it may be useful include autism (Roberts,et al.,2008), stroke vascular, (Tecchio,et al.,2007) schizophrenia,(Rutter,et al.,2009) Parkinson's disease (Stoffers,et al.,2008) and language disorders.

The integration of MEG with other functional techniques such as PET (positron emission tomography, SPECT (single photon emission computed tomography) and fMRI (functional magnetic resonance) and MRS (magnetic resonance spectroscopy ) has been an important contribution to increasing our knowledge of the biologic substrates of the various neurocognitive process and shows the importance of certain areas determine in behaviors. However, these techniques fail to provide information on the functional organization paths of the neuronal networks involved in cognition (Del Rio,et al., 2005).

The capacity of MEG to define the epileptogenic area and its propagation paths has been confirmed by validating the data obtained by using that technique with those obtained by means of electroccorticography or recording made with intracranial electrodes (Del Rio,et al.,2005).

Once of the aspects in which MEG can more quickly define its contributions are without and doubt its application to presurgical study of patients with epilepsy resisted to medical treatment (Shibasaki,et al., 2007).

Fig. 1. A, Biomagnetometer in a electrically shielded room. Patients can be comfortably studied in a seated or supine position.

MEG´s special sensitivity towards the currents discharges in the cerebral sulci and fissures have fostered the study of patients with Landau-Kleffner syndrome, for whom an epileptogenic area is proposed in the persylvian region. In these patients, MEG has had an impotant role for the selection of patients who are candidates to multiple subpial transection treatment (Pateau,et al.,1999).

The contribution of MEG to epilepsy surgery does not simple lie in more accurate or exact definition of the epileptogenic area alone, but, in addition, MEG contributes non invasive alternatives to locate eloquent cortex area that must be preserved during a surgical procedure (Sibasaki,et al., 2007).

#### **1.2 Basic principles of MEG**

98 Neuroimaging – Clinical Applications

brain tumors (Frye,et al.,2009), especially in the functional localization of epileptic focus, another condition in for which it may be useful include autism (Roberts,et al.,2008), stroke vascular, (Tecchio,et al.,2007) schizophrenia,(Rutter,et al.,2009) Parkinson's disease

The integration of MEG with other functional techniques such as PET (positron emission tomography, SPECT (single photon emission computed tomography) and fMRI (functional magnetic resonance) and MRS (magnetic resonance spectroscopy ) has been an important contribution to increasing our knowledge of the biologic substrates of the various neurocognitive process and shows the importance of certain areas determine in behaviors. However, these techniques fail to provide information on the functional organization paths

The capacity of MEG to define the epileptogenic area and its propagation paths has been confirmed by validating the data obtained by using that technique with those obtained by means of electroccorticography or recording made with intracranial electrodes (Del Rio,et

Once of the aspects in which MEG can more quickly define its contributions are without and doubt its application to presurgical study of patients with epilepsy resisted to medical

Fig. 1. A, Biomagnetometer in a electrically shielded room. Patients can be comfortably

of the neuronal networks involved in cognition (Del Rio,et al., 2005).

(Stoffers,et al.,2008) and language disorders.

treatment (Shibasaki,et al., 2007).

studied in a seated or supine position.

al.,2005).

A moving electric charge is always associated with an electric field and concomitant magnetic field surrounding the axis movement fig 2a. Electroencephalogram (EEG) and MEG signals are belied to reflect synchronous postsynatic currents in thousands of parallel apical dendrites. Despite being ultimately due to the same primary currents, EEG and MEG signals differ at some important points (Paetau, 2002). First, only tangential currents, parallel to the head surface, give rise to an extracranial magnetic field. Because the apical dendrites typically run perpendicular to the cortex surface, MEG signal mainly arise in fissure walls fig2b. The EEG signals, on the other hand, are dominated by radial currents, while the tangential ones may require signal averaging to be detected. The complementary sensitivity to current warrants combined use of EEG and MEG whenever possible. Second, in homogeneous tissue conductivity of the human head tends to spread out the signal, but does not alter the magnetic fields. Therefore, tumors, cysts, calcified lesions and skull defects cause less distortion on MEG than EEG signals (Vander,et al., 1998). Third, signal attenuation in EEG is caused by poorly conducting tissue, while the magnetic field fades off proportionally to the second power of the distance from the source. Infant and persons with small heads should preferably be studies with systems composed of two part-head devices adjustable according to the head size or with specially designed baby devices. Fourth, different practical problems hamper data acquisition. MEG sensors are in a rigid helmet and the head as to be kept immobile with respect to the helmet. Long Term recordings or recordings of major motor seizures area far not possible with MEG, but continuous monitoring of the head position may offer relief to some of the movement problems. Finally, MEG and EEG have partly differing artifact profiles: MEG is less sensitive to muscle artifacts than EEG. On the other hand, magnetic materials moving with respiration (Traces from craniotomy drills, some shunt materials, tooth braces, cochlear implants, etc) may cause serious artifacts or even destroy the MEG data.

#### **1.3 MEG in acquired epileptiform regression syndromes**

Acquired epileptic regression syndromes are disabling childhood disorder, were a previously healthy child deteriorates over a week to months. The children may or may not show overt seizures, but their EEG usually displays almost continuous epileptiform spike and wave activity, especially during sleep. In acquired epileptic aphasia or the Landau-Kleffner syndrome (Landau, 1957), the regression affects receptive language and /or auditory perception. Epileptiform spike-and wave discharges appear during the first few weeks, and have been proposed to causally related to cognitive disability. Some LKS children develop giant auditory N100m response with similar auditory cortex sources and

Landau Kleffner Syndrome: Neuroradiology Aspect 101

reactivity as the normal N100m, but with morphology and amplitude identical lo the patient's epileptic spikes (Pateau, 2002). LKS Patient's verbal auditory agnosia can, therefore, be understood as local epilepsy of the auditory cortex, activated by sounds. MEG alone or combined with EEG has proved useful in identifying the sources of epileptic activity in LK, as well as in childhood epileptic autistic regression disorders (Sobel et

In 1957 Landau and Kleffner described six children with acquired aphasia syndrome and epileptic seizures with encephalographic alterations (Landau, 1957). The syndrome had two basic symptoms: on the one hand an acute or sub-acute acquired aphasia in previously normal children, and on the other, a paroxysmal encephalographic plot with spikes and waves more frequently located in region temporal region that may reach an epileptic stage during the slow stage. Convulsive seizures, if shown come before or follow the beginning of the slow speech impairment but these epileptic discharges in the electroencephalogram are invariably present (Guevara Campos & González Guevara, 2007). It may be accompanied by behavior or demeanor disorders, such as hyperactivity, expression of aggressive,

The etiology of the LKS is unknown. Although encephalitis has been proposed as an etiology, some of empirical evidence has raised doubts. For example, the course of LKS is very different from that of Rasmussen chronic encephalitis and temporal lobotomy histology in two cases of LKS was not consistent with encephalitis (Rasmussen & Mc Cann 1968; Coke et al., 1988). Based on the results of conventional angiography in some patients with LKS, Pascual-Castroviejo (Castroviejo et al., 1992) proposed vasculitis as an etiology. These investigators treated patients with calcium blockers with a favorable response. Others have considered whether an underlying autoimmune mechanism may contribute to the pathogenesis of LKS give the fact autoimmune processes may be involved in the pathogenesis of child development disorders and epilepsy (Nesimalova et al., 1992). This idea is supported by Connolly (Connolly et al., 2006). Who reported an increase in IgM autoantibodies to endothelial cells and IgG autoantibodies to myelin basic protein as compared to healthy controls. A small number of brain lesions have been reported in association with the LKS, including neurocysticercosis (Bhatia et al., 1994), toxoplasmosis (Michalowiez et al., 1989), temporal lobe astrocytoma (Solomon et al., 1993), and temporal lobe glioma (Solomon et al., 1993). The increased risk of LKS in monozygoyic twins and siblings suggests a genetic etiology (Feekery et al., 1993). Thus, it is very likely that the etiology of the LKS is variable with several etiologies. It would be useful to classify LKS as cryptogenic or symptomatic. The cause of epilepsy and continuous aphasia still remains a

Single photon emission computed tomography imaging demonstrated hypometabolism in 22 of his 25 patients (O´Regan et al., 1998), suggested that aphasia occurs as a manifestation of a hypometabolic encephalopathy secondary to a local postictal state (O´Regan et al., 1998). Positron emission tomography has shown dynamic changes in the metabolism of glucose in

al.,2000;Muñoz Yunta et al.,2008).

**2. Landau-Kleffner syndrome**

rebelliousness and autistc features.

mystery (Deonna, 1991).

**3.1 Aphasia**

**3. Clinical manifestations**

Fig. 2. Physical basis of MEG signals. (a) The intracellular current I in the apical dendrite of a pyramidal cell is associated with a surrounding magnetic field B. (b) In the brain, pyramidal cells typically are perpendicular to cortex surface, and may be radial (white arrows), oblique or tangential (dark arrows) to the scalp. Only the tangential currents and the tangential component of oblique currents contribute to the extracranial magnetic field, which can be detected by sensitive SQUID magnetometers. (c) Dipolar magnetic field pattern viewed above. B in indicates the magnetic flux into the head and B out the flux out from the head. An equivalent current dipole (ECD; the thick black arrow) represents the concerted action lines of all fissural dipoles. Its orientation is parallel to the isofield lines and it is located underneath the steepest gradient halfway between the in- and out-flowing flux. Its depth determines the distance between the two extremes, and its strength is proportional to the number of active pyramidal cells.

reactivity as the normal N100m, but with morphology and amplitude identical lo the patient's epileptic spikes (Pateau, 2002). LKS Patient's verbal auditory agnosia can, therefore, be understood as local epilepsy of the auditory cortex, activated by sounds. MEG alone or combined with EEG has proved useful in identifying the sources of epileptic activity in LK, as well as in childhood epileptic autistic regression disorders (Sobel et al.,2000;Muñoz Yunta et al.,2008).

#### **2. Landau-Kleffner syndrome**

100 Neuroimaging – Clinical Applications

Fig. 2. Physical basis of MEG signals. (a) The intracellular current I in the apical dendrite of a pyramidal cell is associated with a surrounding magnetic field B. (b) In the brain, pyramidal cells typically are perpendicular to cortex surface, and may be radial (white arrows), oblique or tangential (dark arrows) to the scalp. Only the tangential currents and the tangential component of oblique currents contribute to the extracranial magnetic field, which can be detected by sensitive SQUID magnetometers. (c) Dipolar magnetic field pattern viewed above. B in indicates the magnetic flux into the head and B out the flux out from the head. An equivalent current dipole (ECD; the thick black arrow) represents the concerted action lines of all fissural dipoles. Its orientation is parallel to the isofield lines and it is located underneath the steepest gradient halfway between the in- and out-flowing flux. Its depth determines the distance between the two extremes, and its strength is proportional to the

number of active pyramidal cells.

In 1957 Landau and Kleffner described six children with acquired aphasia syndrome and epileptic seizures with encephalographic alterations (Landau, 1957). The syndrome had two basic symptoms: on the one hand an acute or sub-acute acquired aphasia in previously normal children, and on the other, a paroxysmal encephalographic plot with spikes and waves more frequently located in region temporal region that may reach an epileptic stage during the slow stage. Convulsive seizures, if shown come before or follow the beginning of the slow speech impairment but these epileptic discharges in the electroencephalogram are invariably present (Guevara Campos & González Guevara, 2007). It may be accompanied by behavior or demeanor disorders, such as hyperactivity, expression of aggressive, rebelliousness and autistc features.

The etiology of the LKS is unknown. Although encephalitis has been proposed as an etiology, some of empirical evidence has raised doubts. For example, the course of LKS is very different from that of Rasmussen chronic encephalitis and temporal lobotomy histology in two cases of LKS was not consistent with encephalitis (Rasmussen & Mc Cann 1968; Coke et al., 1988). Based on the results of conventional angiography in some patients with LKS, Pascual-Castroviejo (Castroviejo et al., 1992) proposed vasculitis as an etiology. These investigators treated patients with calcium blockers with a favorable response. Others have considered whether an underlying autoimmune mechanism may contribute to the pathogenesis of LKS give the fact autoimmune processes may be involved in the pathogenesis of child development disorders and epilepsy (Nesimalova et al., 1992). This idea is supported by Connolly (Connolly et al., 2006). Who reported an increase in IgM autoantibodies to endothelial cells and IgG autoantibodies to myelin basic protein as compared to healthy controls. A small number of brain lesions have been reported in association with the LKS, including neurocysticercosis (Bhatia et al., 1994), toxoplasmosis (Michalowiez et al., 1989), temporal lobe astrocytoma (Solomon et al., 1993), and temporal lobe glioma (Solomon et al., 1993). The increased risk of LKS in monozygoyic twins and siblings suggests a genetic etiology (Feekery et al., 1993). Thus, it is very likely that the etiology of the LKS is variable with several etiologies. It would be useful to classify LKS as cryptogenic or symptomatic. The cause of epilepsy and continuous aphasia still remains a mystery (Deonna, 1991).

#### **3. Clinical manifestations**

#### **3.1 Aphasia**

Single photon emission computed tomography imaging demonstrated hypometabolism in 22 of his 25 patients (O´Regan et al., 1998), suggested that aphasia occurs as a manifestation of a hypometabolic encephalopathy secondary to a local postictal state (O´Regan et al., 1998). Positron emission tomography has shown dynamic changes in the metabolism of glucose in

Landau Kleffner Syndrome: Neuroradiology Aspect 103

(independent) spike foci and secondary spikes (Paetau, 2009) MEG and EEG are necessary for the spatial and temporal understanding of the perisylvian region and epileptic networks

The 4 potential roles for MEG in the localization of the ictal onset zones (IOZ) and functional cortex: 1) MEG confirmations of localization based on traditional noninvasive methods, allowing epilepsy surgery to proceed without long term intracaneal EEG monitoring; 2) MEG demonstration of bilateral, multifocal, or diffuse ictal onset, indicating an unfavorable candidate for epilepsy surgery; 3) MEG locations adjacent to or distant from that of traditional methods or focally , when traditional methods suggest multifocal activity, potentially altering clinical decision making regarding epilepsy surgery ; and 4)MEG localization of eloquent cortex to guide surgical trajectory. These data will serve to refine prospective studies on the optimal use of MEG in the localization of the IOZ and functional