GABAA, Glycine and Glutamate Receptors
GABAA receptors are structurally homologous to nicotinic receptors but are permeable to chloride ions instead of sodium and potassium. They mediate fast inhibitory transmission and are the sites of action of benzodiazepines and other anti‐epileptic, and anxiolytic drugs. Loss‐of‐function mutations have been reported in epilepsy.
Glycine receptors also homologous to GABAA mediate fast inhibition in the spinal cord and brainstem. AD or AR loss‐of‐function mutations of GLRA1 cause familial hyperekplexia.
Glutamate receptors mutations have been described in schizophrenia, and in rolandic epilepsy.
Acquired Channelopathies
Several autoimmune disorders affect ion channels. Antibodies recognise extracellular epitopes, for example AChRs, P/Q‐type calcium channels, glycine and NMDA receptors. Aquaporin 4 (see antibodies in Devic’s, Chapter 11) is a transmembrane protein that permits the flow of water between glial cells. The way that an ion channel is affected is similar in both an acquired and hereditary channelopathy – as one might expect because each ion channel has a limited repertoire. More antibody‐channel interactions are likely to be discovered and to be of significance.
Acknowledgements
I am most grateful to Dimitri Kullmann, Henry Houlden & Michael Lunn for their contribution to Neurology A Queen Square Textbook Second Edition on which this chapter was based. I am also indebted to Simon Farmer & David Choi who wrote in Chapter 16 about spinal embryology in Neurology A Queen Square Textbook Second Edition.
Further Reading
1 Kullman D, Houlden H, Lunn M. Mechanisms of neurological disease: genetics, autoimmunity and ion channels. In Neurology A Queen Square Textbook, 2nd edn. Clarke C, Howard R, Rossor M, Shorvon S, eds. John Wiley & Sons, 2016. There are numerous references.
Also, please visit https://www.drcharlesclarke.com for free updated notes, potential links and references as these become available. You will be asked to log in, in a secure fashion, with your name and institution.
4 Examination, Diagnosis and the Language of Neurology
My purpose here is to outline how I approach day‐to‐day neurology:
To provide a framework for examination, diagnosis and investigation
To introduce terminology – the language and vocabulary we use.
There is some distance between anatomy, science, diagnosis and the words we use to communicate clinical features. I try to fill these gaps. Our first purpose is to answer one question: is there a recognisable disease? In no other speciality are clinical patterns more important, nor are they more reliable. Despite advances in imaging, neurogenetics and neuropathology, we follow a traditional approach:
Assemble clinical observations – history, symptoms and physical signs, and assess investigations.
Recognise, by sifting these, the site of the problem, and if possible a disease.
Good neurology is about getting this right. Failure to follow this approach can lead to over‐investigation or missing a serious disease.
Elements of Diagnosis
Diagnosis is the product of the history and examination. Many find neurology hard, both because of this interplay and also because of its breadth. In some conditions, such as migraine, a faint or a seizure, we rely on narratives. There are typically no physical signs. In others, examination is pivotal, for example signs of a spastic paraparesis. However, despite its sophistication the nervous system has a relatively limited repertoire. For example, a headache can be similar whether the problem is benign or sinister.
Try to answer:
Do the history and signs point to the site of the lesion, or lesions or to a system?
Do the time course and character of the findings point to a recognisable disease?
History
The narrative, from the patient, and witnesses provides vital data. How to take a present, past and family history is assumed. Pitfalls occur in three areas:
First, vividness comes from a verbatim account. Abbreviations are rife. ‘Fitted on way to A&E – bitten tongue….’ is familiar medical shorthand. The inference is a generalised tonic–clonic seizure, but it does not indicate what was actually said:
I was standing on the 73 bus near King’s Cross first thing taking mum to hospital. I felt all dizzy …. my eyes went all funny, my legs went weak and out I went. I came to on the floor, in a pool of blood. Mum says I fainted. But then the ambulance came and they said I was shaking. I’d bitten my lip….I was right as rain in a minute but they said they thought I’d had a fit.
Syncope, a simple faint, is obvious.
Secondly, identify temporal patterns:
Intermittent events with recovery. Common: epilepsy, migraine, syncope and TIAs. Rarer: paroxysmal dyskinesias.
Intermittent, with relapses and remissions: MS is the typical example.
Progressive, chronic: neurodegenerative and neoplastic disorders.
Acute or subacute and progressive: usually infective, vascular or inflammatory.
Acute onset, single insult, with some recovery. Stroke is the prime example. Guillain–Barré and traumatic brain injury are others.
The long time scale can sometimes be forgotten – prolonged febrile convulsions in infancy or a head injury long ago can be of relevance to later seizures. Family history may be relevant.
Thirdly, one’s own attitude – the balance between critical appraisal and sympathy. Judgmental approaches interfere with diagnosis, and lead to complaints. Our principal purpose is to help.
Many patients find unfamiliar questions difficult. There is no such thing as a ‘hopeless historian’ – it’s the neurologist’s fault. Patients today are well‐informed, but the unsympathetic neurologist remains well described. Patients do actually suffer from their complaints. That first visit carries a burden – a serious diagnosis is often in mind. Patients and relatives hang upon single comments. Depression and anxiety are common.
Nature of Symptoms
Foundations of neurology emphasised distinctions between positive and negative or primary and secondary phenomena, though these are not rigid. Many brain, cord, root and nerve lesions are destructive, that is with negative, primary effects such as paralysis. Destructive lesions may also cause positive, secondary phenomena, typically release of neuronal inhibition, such as exaggerated tendon reflexes. Positive also describes irritative phenomena, such as seizures.
Symptoms can thus be of two types:
Primary (direct) abnormalities, often negative: one part fails to work. Primary abnormalities can also be positive (irritative) – focal seizures from a glioma, or pain in the distribution of