Neurology. Charles H. Clarke

for its pathogenesis, or diseases where antibodies are simply markers.

      Neurological Disease with Pathogenic Autoantibodies

      Myasthenia gravis (MG), Guillain–Barré syndrome, Lambert–Eaton myasthenic syndrome (LEMS), some autoimmune encephalitides and probably stiff person syndromes are examples of B‐cell mediated diseases in which antibodies cause the clinical picture.

      In MG, antibodies to the post‐synaptic acetylcholine receptor (AchR) cause a complement‐dependent disruption of the post‐synaptic neuromuscular junction and fatigable weakness. The unsolved question remains: what initiates anti‐AchR antibody production?

      GBS: in the acute motor axonal neuropathy (AMAN) GBS variant, initiation of the antibody response is better understood. Some strains of Campylobacter jejuni have ganglioside‐like epitopes on their lipo‐oligosaccharide coat. Infection in individuals who have impaired self‐tolerance and in whom sufficient adjuvant stimulation exists, make antibodies to their own peripheral nerve gangliosides. These antibodies have complement‐dependent mechanisms that alter membrane characteristics at nodes of Ranvier and elsewhere, and thus damage both axons and myelin.

      Similar mechanisms presumably exist in the common demyelinating Guillain–Barré syndrome.

      Some CNS diseases also appear to be directly antibody mediated:

       Antibodies form to the voltage‐gated potassium channel complex to two of its components: LGI1 and Caspr2. Antibodies to LGI1 cause a form of limbic encephalitis. Antibodies to Caspr2 produce Morvan’s syndrome – peripheral nerve hyperexcitability, psychiatric features and sleep disturbance.

        Antibodies to N‐methyl‐D‐aspartate (NMDA) receptors cause an encephalitis, mainly in women, associated with antibodies against NR1 or NR2 NMDA subunits.

       Antibodies to aquaporin‐4, the water channel protein, and possibly to myelin oligodendrocyte glycoprotein (MOG), are associated with Devic’s disease (Chapter 11).

      Neurological Disease with Systemic Disorders and Autoantibodies

      Several diseases have antibodies that may have both systemic effects and effects on the nervous system. In others, antibodies are central to diagnosis but of questionable relevance to pathogenesis.

      Anti‐neutrophil cytoplasmic antibodies (ANCA) are associated with some vasculitides. Although antibodies may attack neutrophils, for example in granulomatosis with polyangiitis (GPA), they are not essential to the pathogenesis.

      Antibodies to extractable nuclear antigens (ENA) are associated with primary and secondary Sjögren’s syndrome – that causes a sensory neuronopathy.

      Antibodies to phospholipid and cardiolipin are associated with the antiphospholipid syndrome – that may cause a disorder of coagulation, or in some cases an MS‐like condition.

      In paraneoplastic conditions there is overlap between humoral and T‐cell mediated disease, but the antibody tends to define the syndrome.

      Anti‐Hu, anti‐Yo and anti‐Ri, associated with disorders such as sensory ganglionopathies, limbic encephalitis and the opsoclonus‐myoclonus syndrome are also associated with tumour types such as small cell cancers, breast and ovarian tumours.

      T‐Cell‐Mediated Neurological Disease

      T‐cell‐mediated disease is difficult to define, and targets of T‐cell receptors hard to isolate. These conditions are less reversible than B‐cell‐mediated disease:

       In paraneoplastic diseases there are T‐cytotoxic mechanisms of cell injury, such as with anti‐Hu, anti‐Yo and anti‐Ri.

       Cerebral and peripheral nerve vasculitis: the final path to tissue damage involves T‐cell infiltration.

       MS is the best‐described T‐cell disorder, but among the most mysterious. Whether the process of myelin and axonal destruction is a neurodegeneration, primarily autoimmune, and/or driven by some viral pathogen remains unknown.

       CIDP (Chronic Inflammatory Demyelinating Polyneuropathy) is an example of T‐cell‐mediated PNS disease. There are deficiencies in the autoimmune regulator protein AIRE, reduced T‐regulatory mechanisms, failure of Fas‐Fas ligand lymphocyte down‐regulation and mixed Th1 and Th2 cytokine profile up‐regulation, both in serum and endoneurium. B‐cell‐mediated pathways are also involved.

      Cytokine‐Driven Processes

Primary cytokine‐driven processes are also far from clearly defined. One example occurs in POEMS (polyneuropathy, organomegaly, endocrinopathy, M‐protein and skin changes). It appears that central processes driving the disease are unregulated vascular endothelial growth factor (VEGF) and IL‐6 production, possibly exacerbated by hypoxia‐induced factor 1α (HIF‐1α). This unregulated cytokine drive causes proliferation and maturation of B cells and increased cytokine production.

      Immunomodulation, Immunosuppression and Replacement Therapy

       Intravenous immunoglobulin (IVIg) acts by multiple mechanisms, by non‐specific removal of soluble immune factors and possibly interferons. Interference with B‐ and T‐cell interactions, macrophages and complement is important.

       Plasma exchange removes low molecular weight solutes including cytokines and antibodies, especially IgG – quick and effective in GBS, systemic vasculitides and antibody‐mediated encephalitides.

       Interferons act at least in part via modulation of the cytokine network.

       Steroids, oral azathioprine, methotrexate, mycophenolate, and ciclosporin and IV cyclophosphamide immunosuppress non‐selectively.

       IVIg is a replacement therapy in hypogammaglobulinaemias.

      Discussion related to therapies in MS: see Chapter 11.

      Targeted Ablative Therapies

      Anti‐CD20 and anti‐CD52 monoclonal antibodies are increasingly used, sometimes in combination with other immunosuppressants such as rituximab or methotrexate. Idiosyncratic rare complications are limiting factors. For example, PML (progressive multifocal leukoencephalopathy) is a known, usually fatal complication of rituximab, natalizumab and others. When death or severe disability is not an outcome of the primary disease, these medications are ethically questionable.

      Specifically Targeted Molecules

      Anti‐TNF, anti‐VEGF and anti‐IL‐6: some of these are targeted therapies, such as etanercept, widely used in rheumatoid. Others are antibodies with anticytokine activity such as bevacizumab which acts as an anti‐VEGF agent, or tocilizumab which is anti‐IL‐6.

Ion Channels and Inherited Mutations

      Changes in ion channels can explain clinical features. Monogenic channelopathies provide insights into disease mechanisms and whilst they are rare, they frequently have features seen in common sporadic disorders such as epilepsy and migraine. The study of channelopathies can identify signalling pathways in many diseases. One feature is that many channelopathies cause discrete paroxysms; function returns to normal between attacks. Most channelopathies are AD inherited but this may simply reflect that AR disorders are hard to identify.

      Channelopathies can present in all areas of neurology. The broad groups are summarised here.

      Migraine,