support for the diagnosis of Alzheimer’s disease versus frontotemporal dementia and other degenerative diseases (Chapter 5).
CSF Cells and Other Constituents
CSF is essentially acellular. Few cells are found in normal CSF: most laboratories quote <5 white cells/mm3 as normal, but any cells should provoke suspicion. Cells are typically lymphocytes: macrophages or neutrophils are almost certainly disease‐related. Red blood cells are always abnormal, though the commonest cause is a traumatic tap. Cytology/flow cytometry may be needed, for example in malignant meningitis and haematological malignancy.
Bacteria and fungi can be isolated by culture and seen on microscopy. Viruses: PCRs are specific but variably sensitive. Whole genome and next generation sequencing techniques are available. Oligoclonal banding pattern can identify the relative production of monoclonal or oligoclonal responses, useful in inflammatory diseases. The antigenic target in MS of oligoclonal bands remains a mystery.
Immune Nervous System Diseases
While immunology, like genetics and ion channels, is a part of every chapter in this book, it is often difficult to make dogmatic statements. Here are examples where immune pathogenesis is truly relevant.
Antibody‐Mediated Diseases
Antibody‐mediated diseases can be divided either into those where the antibody defines the disease and is responsible 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,
