Chapter
9 Immune diseases
Table 9.1 Diagnostic criteria for multiple sclerosis
Presentation Additional studies required 2 or more attacks
2 or more objective clinical lesions
None (desirable, must be consistent with MS)
2 or more attacks
1 objective clinical lesion Demonstration of a dissemination in space by MRI, or positive CSF and at least 2 MRI lesions, or a new attack in another site 1 attack
2 or more clinical lesions Dissemination in time demonstrated by MRI or a second clinical attack 1 attack
1 objective clinical lesion Dissemination in space demonstrated by MRI or positive CSF with at least 2 MRI lesions
Dissemination in time demonstrated by MRI or a second clinical attack Neurological
progression suggestive of MS
Positive CSF
Dissemination in space demonstrated by brain MRI (9 lesions or more), or at least 2 spinal cord lesions, or 4–8 brain lesions and 1 spinal cord lesion, or positive visual evoked potential (VEP) with 4 to 8 MRI lesions, or positive VEP with fewer than 4 brain lesions with 1 spinal cord lesion
Dissemination in time demonstrated by MRI or continued progression for 1 year
cerebrospinalfluid (CSF) (see below), the presence of two or more lesions is sufficient to disclose dissem- ination in space. New T2- or gadolinium-enhancing lesions appearing at least 3 months after the onset of the clinical event satisfy the MRI criteria for dis- semination in time. Failure to perform follow-up MRI in patients with clinically isolated syndromes may become a practical difficulty for compliance with the criteria (McHugh et al.,2008).
Differential diagnosis
Several disorders can mimic MS:
! Neuromyelitis optica (NMO) is characterized by optic neuritis and myelitis. Revised diagnostic criteria for definite NMO also require at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion (three or more segments in length), onset brain MRI
nondiagnostic for multiple sclerosis, or NMO immunoglobulin (Ig) G seropositivity (NMO-IgG, an autoantibody targeting aquaporin-4, is a biomarker for NMO) (Wingerchuk et al.,2006).
! Other causes of optic neuritis
! Transverse myelitis
! The group of vasculitis disorders affecting the central nervous system
! Fabry disease (Saip et al.,2007): patients present with unexplained stroke-like episodes,
angiokeratomas, and proteinuria (see Chapter8)
! Fulminant or acute inflammatory-demyelinating diseases, such as the Marburg variant of MS, Bal´o concentric sclerosis, Schilder disease, and acute disseminated encephalomyelitis (see Chapter11)
! Erdheim-Chester disease (see Chapter13)
! Congenital adrenal hyperplasia is an inherited recessive disorder of adrenal steroidogenesis caused by a total or partial deficiency in
21-hydroxylase due to a deletion of or mutations in the CYP21 gene (Bergamaschi et al.,2004).
Impaired cortisol biosynthesis results in corticotropin hypersecretion. Patients may present with cerebellar signs. Repeated brain MRI shows focal white matter lesions in periventricular areas, the corpus callosum, the cerebellum, and the brainstem.
Neurophysiology
Multimodality evoked potentials (visual evoked potentials, somatosensory evoked potentials, auditory evoked potentials, and motor evoked potentials) document spatial dissemination of lesions. These lesions may be clinically silent. Evoked potentials are particularly useful when symptoms are atypical without any objective impairment and when symp- toms have already recovered at the time of clinical examination (Fischer et al., 2001). Transcranial magnetic stimulation measures have a high sensitivity in detecting lesions in MS, and abnormalities in central motor conduction time may correlate with motor impairment and disability (Chen et al.,2008).
Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathways.
About half of the patients have impaired sympa- thetic skin responses. Sudomotor regulation failure
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might be correlated with the total lesion volume in the whole brain and focal lesion volumes in the temporal lobe, in the pons, and in the cerebellum (Saari et al., 2008).
Neuroimaging
MRI has a unique sensitivity to demonstrate the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord (Rovira & Le´on, 2008).
Conventional MRI techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences, are sensitive in detecting MS plaques and provide a quan- titative assessment of inflammatory activity and lesion load. However, there is often a discrepancy between clinical efficacy and MRI-based estimation of the effects of treatments.
T2-weighted images of the optic nerve usually show a hyperintense lesion in optic neuritis, and gadolinium enhancement is seen in the acute attack (Kolappan et al., 2009). Quantifying atrophy of the optic nerve using MRI gives an indication of the degree of axonal loss. Magnetization transfer ratio (MTR) of the optic nerve provides an indication of myelination, and diffusion tensor imaging of the optic nerve/optic radiation gives information about the involvement of the visual white matter tracts. Infratentorial T1- weighted hypointense lesions are often found on brain MRI in patients with MS and chronic cerebellar ataxia.
The Expanded Disability Status Scale score correlates with both the number and the volume of these lesions.
Lesions may predominate in the cerebellar peduncles in some patients. Overall, cerebellar lesions are less fre- quent in late-onset MS as compared with young-onset MS (Kis et al.,2008).
Cortical and subcortical atrophy in MS relates to clinical outcomes. Voxel-based automated studies for brain reconstruction show that cerebellum white mat- ter volumes are significantly lower in MS from the earliest clinical stages (Ramasamy et al., 2009). MS patients have lower volumes of thalamus as well as cortical thinning, which increases as the disease pro- gresses.
Diffusion tensor MRI scans might become a useful tool for detecting abnormalities which are not appar- ent in T2-weighted sequences. In primary progressive MS patients, mean diffusivity changes involve several cortical-subcortical structures in all cerebral lobes and the cerebellum (Ceccarelli et al., 2009). An overlap between decreased white matter fractional anisotropy
and increased white matter mean diffusivity is found in the middle cerebellar peduncles.
CSF studies
More than 95% of patients have positive oligoclonal bands or raised IgG index in the CSF.
Neuropathology
Plaques are found in both gray and white matter.
The most likely sites are periventricular and peri- aqueductal areas. Acute plaques typically spread out from the post-capillary venules. Early plaques are usu- ally hypercellular, with diffuse demyelination, swollen astrocytes, and attack of the myelin by macrophages.
Inflammation and edema will slowly decrease there- after. The cerebellar cortex is a predilection site for demyelination, in particular in patients with pri- mary and secondary progressive MS (Kutzelnigg et al., 2007). In these patients, about 40% of the cerebellar cortical area is affected. Cerebellar cortical demyelina- tion occurs mainly in a band-like manner.There is no correlation between demyelination in the cortex and the white matter.
Pathogenesis
MS is characterized by immune attack(s) against myelin and myelin-forming cells in the central ner- vous system. Multiple causes have been suggested. In particular, damage to oligodendrocytes might follow a viral or a bacterial infection, myelin repair by oligo- dendroglia might be defective, and MS might develop following complex genetic–environmental interac- tions. Increased family risks range from 300-fold for monozygotic twins to 20- to 40-fold for biological first-degree relatives (Ebers et al.,1995). MRI shows abnormalities consistent with demyelination in some monozygotic and dizygotic co-twins who are clini- cally unaffected (Mumford et al.,1994). Episodes of demyelination and axonal damage are mediated pri- marily by CD4-positive T-helper cells with a pro- inflammatoryTh1 phenotype, macrophages, and sol- uble mediators of inflammation. Experimental allergic encephalomyelitis is a commonly used model of MS in animals.
Treatment
Therapies are summarized in Table 9.2. It is now possible to diagnose patients with MS earlier than
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Table 9.2 Treatment of multiple sclerosis Corticosteroids
Beta-interferons Glatiramer acetate Plasma exchange Immunosuppressants Monoclonal antibodies Cladribine
Treatment of tremor (deep brain stimulation, thalamotomy)
previously due to the integration of MRI parameters into the diagnostic criteria.This provides a window of opportunity to treat patients before clinically manifest tissue destruction (Tintor´e,2009).
Corticosteroids remain a mainstay of treatment for acute relapses in MS and optic neuritis (Tumani, 2008). High-dose short-term intravenous steroid therapy (methylprednisolone 500–1000 mg/day for 3–5 days) provides symptomatic relief, improves motor function, and accelerates the recovery, but there is no evidence that long-term corticosteroid treatment delays progression of long-term disability.
Young-onset MS patients usually respond to steroids to a significantly greater degree as compared with late-onset MS patients (Kis et al.,2008). Oral applica- tions of steroids may be proposed for the treatment of exacerbations if intravenous administration poses practical problems (Tumani,2008). Acute monitoring in patients with diabetes mellitus, patients receiving anticoagulation, or those having a history of glaucoma is recommended. Behavioral disturbances and gastri- tis are potential side effects. Supplements of vitamin D and calcium (1 g/day) may be added in patients with osteoporosis. Some authors suggest bisphosphonates or calcitonin.
Patients suffering from severe steroid-resistant relapses may benefit from plasma exchange.This ther- apy has become an integral part of escalating relapse therapy in relapsing-remitting MS (Linker & Gold, 2008). Best effects can be expected when plasma exchange is administered within 4 to 6 weeks after onset of symptoms and require usually at least three sessions. Possible complications are related to the use of central venous access (infections, thrombosis, pneu- mothorax), anticoagulation, and hypocalcemia due to citrate infusion.
Beta-interferons and glatiramer acetate, a com- plex heterogenous mixture of polypeptides with
immunomodulatory activity, can decrease the fre- quency and severity of relapses. Patients with relaps- ing multiple sclerosis randomized to interferon-beta 1b or glatiramer acetate show similar MRI and clinical activity (Cadavid et al.,2009). Patients treated with an interferon-beta should be monitored systematically for the appearance of neutralizing antibodies. Interferon- beta treatment should be discontinued in case of per- sistent neutralizing antibodies.
Monoclonal antibodies such as natalizumab might reduce relapses and progression in relapsing-remitting and secondary progressive MS. The risk of progres- sive multifocal leukoencephalopathy (see also Chap- ter 11) is increased with this agent (Langer-Gould et al., 2005). The interleukin-2 receptor antagonist daclizumab leads to both clinical improvement and a reduction in MRI activity (Rose et al.,2007).
Brief immunosuppression with mitoxantrone fol- lowed by maintenance therapy with glatiramer acetate might provide a synergistic effect on control of disease activity (Boggild,2009).
Cladribine is a novel immunosuppressant cur- rently under investigation. Cladribine triggers anti- inflammatory effects on MRI evaluation, but may not influence the neurodegenerative process (Filippi et al., 2000).
Fatigue may improve with modafinil and gla- tiramer acetate (Lange et al.,2009; Ziemssen,2009).
Sildenafil (50–100 mg) is effective in the treatment of sexual dysfunction in some patients.
Paroxysmal dysarthria responds to carbamazepine (Blanco et al.,2008).
Improvement of tremor with medical treatment (clonazepam, gabapentin, topiramate, primidone Mysoline@) is often modest. Stereotactic surgery targeting the vim nucleus of the thalamus is success- ful in alleviating MS tremor. Tremor with a poor response to vim deep brain stimulation monotherapy may respond favorably to vim plus ventralis oralis anterior/ventralis oralis posterior (Foote et al.,2006).
Stimulation of the zona incerta nucleus may have the advantage of improving proximal components of tremor (Plaha et al., 2008). Gamma knife radio- surgical thalamotomy is an effective alternative to stereotactic surgery (Mathieu et al., 2007). Patients experience improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawings. Transient contralateral hemiparesis is a potential complication which may respond to steroids.
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Recent studies suggest that vagus nerve stimulation might improve postural cerebellar tremor associated with MS, probably by acting at multiple levels in the brainstem (Marrosu et al.,2007).
Repetitive transcranial magnetic stimulation over the motor cortex in MS subjects with cerebellar symp- toms improves hand dexterity, but the therapeutical implications remain to be determined.