OHCM 10e, p. 822.Electroencephalogram: abnormalities
Electroencephalogram: in epilepsy
Electroencephalogram: how to use
Electroencephalogram: invasive techniques
Sensory evoked potentials or responses
Transcranial magnetic stimulation
Neurological investigation of sphincter disturbance
Diagnostic and prognostic antibodies, and other markers in blood and urine
•Polyradiculitis, polyneuritis.
Note: in general, a −ve CT does not exclude an SAH.
•Suspected malignancy with meningeal involvement.
•High (e.g. idiopathic or ‘benign’ intracranial hypertension (IIH)).
•Low (e.g. ‘low pressure’ headache).
•Normal pressure hydrocephalus (NPH) (not particularly helpful).
•To seek specific antibodies/markers in CSF, e.g.
•Lactate in mitochondrial cytopathies.
•Decide exactly what investigations you want. If necessary, alert the appropriate laboratories and organize transport of samples. In particular, samples for xanthochromia and cytology should be rapidly taken to the laboratory to be spun down.
•If the patient is also due to have a neuroradiological investigation with contrast and an LP is not urgent, delay the LP until after the scan, as there may be diffuse meningeal enhancement after the LP.
•If the patient is extremely anxious, he may benefit from 5–10mg of oral diazepam prior to the LP.
1.Explain to the patient what you are about to do.
2.Arrange all your equipment on a sterile tray, including assembled CSF manometer.
3.Position the patient on his side, with the back perpendicular to the bed, at the edge of a firm bed. Place the head on one pillow. Draw the knees up, and place one pillow between them.
4.Adjust the height of the bed, so that you are comfortable.
5.Identify the bony landmarks. L3/L4 space is in line with the iliac crests and is most commonly used. L2/L3 to L5/S1 are also used. If you like, mark the target space with the imprint of your thumb nail. Take time over these first four stages.
6.The insertion of the needle should be a sterile procedure. Clean the skin over the lower back. Don sterile gloves and mask.
7.Insert a little (0.25–0.5mL) LAn—too much can obscure the bony landmarks.
8.Pass the LP needle horizontally into the space, with the tip angled at about 10–15° (towards the umbilicus), in the midline horizontal plane. At all times, the stylet should be fully inserted and the bevel of the needle facing up.
9.Slight resistance should be felt as the needle passes through the ligamentum flavum and dura, and then a ‘give’ as it enters the subarachnoid space.
10.Slowly withdraw the stylet. CSF drops should appear.
11.If CSF does not appear, reinsert the stylet and slightly rotate the needle—this sometimes frees it of obstructing nerve roots. A gentle cough from the patient can also help.
12.If the needle encounters bone, or the patient complains of pain shooting down the leg, check the position of the needle (is it in the midline? Is it angled correctly?) and then withdraw it entirely.
13.Insert a fresh needle, correcting for any error noted above.
14.If this second pass is unsuccessful, withdraw the needle and inform the patient. If he is happy for you to proceed, then attempt the LP in another space, repeating all steps from 4 down. Use a fresh needle.
15.If you fail again, explain to the patient and seek a more experienced operator to perform the LP. Multiple failed attempts are painful and discouraging (to both you and your patient).
16.If a more experienced operator fails, ask your friendly radiologist to do it under X-ray guidance, but give him the help he requests and precise instructions about the samples required.
17.When CSF collection is complete, gently pull out the needle and place a sterile dressing over the insertion site.
As soon as the CSF starts to flow, attach the pre-assembled manometer. Wait until the CSF stops rising. If the patient is very anxious, or uncomfortable, a falsely raised opening pressure may be recorded. Sometimes having the patient slightly relax his legs will help. Using the 3-way tap, let the CSF run into your first prelabelled tube (do not waste the CSF!). Having collected all the CSF you require, if the opening pressure was elevated, note the closing pressure. If the opening pressure is expected to be very raised, e.g. in suspected or confirmed idiopathic (benign) intracranial hypertension, then two or more manometers should be pre-assembled, as the pressure may exceed 40mmCSF.
•As always, tailor your investigations to the clinical picture. If you are just checking the CSF pressure, then no samples need necessarily be collected. If you suspect an SAH, collect three samples in sequentially labelled bottles and promptly hand-carry to the laboratory for quantitative estimation of xanthochromia and Hb breakdown products. If you are looking for evidence of malignant cells, then at least one sample should be sent to the laboratory promptly for cytology.
•To avoid contamination, allow the microbiology laboratory to split samples, rather than attempting this yourself.
•Collect at least ten drops in each bottle. The microbiology and cytology laboratories in particular will thank you for greater volumes.
•As soon as the CSF is collected, a blood sample should be obtained (if necessary) for glucose and OCB detection.
Sometimes there is a dry tap if the CSF pressure is too low to distend the lumbar cistern. This can sometimes be overcome by performing the LP with the patient sitting on a firm reversed chair, leaning forward to bend over its back. This manoeuvre maximizes the separation of the vertebrae. Again, the needle should be angled slightly (10°) upward relative to the spine at that point. This position does not allow accurate measurement of CSF pressure.
A 22G needle usually appropriate. Needles with larger bores tend to cause a greater CSF leak (and thus more headache). Some advocate even finer needles, but these make the collection of CSF take too long. ‘Blunt’ anaesthetists’ needles reduce the risk of post-LP headache.
Record what you did in the notes after the procedure (e.g. if >1 pass was required; which space you used), the opening and closing CSF pressures, and what investigations you have requested. Note the appearance of the CSF (if normal, it will be clear and colourless). If the CSF appears bloody, record this and whether the final bottle collected is clearer than the first.
•Non-communicating hydrocephalus.
•Cerebral oedema (if in doubt, cranial imaging should be performed first).
•Uncorrected bleeding diathesis/anticoagulant use.
•Caution: if previous lumbar spine surgery or known anatomical abnormalities.
Note: it is usually safe and appropriate to perform an LP in suspected meningitis, unless there are specific clinical features to suggest raised ICP, in which case cranial imaging should be performed first.
•Usually starts within 24h of LP.
•May last from a few hours to 2 weeks, but typically several days.
•Probably related to persistent CSF leak via the dural tear; therefore, tends to have ‘low pressure’ characteristics (frontal, worse on sitting up, better on lying down). There may be mild meningism and nausea.
Treatment has traditionally involved bed rest, analgesia, and the encouragement of plenty of fluids.
•If nausea is a major problem, the patient may require IV fluids.
•Rarely, if the headache is severe and persistent, then an anaesthetist may place an autologous blood patch to ‘plug’ the dural tear. Surgical intervention is very rarely required.
A variety of causes of post-LP backache exist; these may usually be treated conservatively.
Very rare if a sterile technique is used. Occasionally may occur if the needle passes through a region of infection. Meningitis typically develops within 12h. Very rarely, there may be an epidural abscess or vertebral osteomyelitis. Treat with appropriate antibiotics and, if necessary, surgery.
•Uncal or cerebellar herniation may occur, particularly in the presence of a posterior fossa mass. ►►An LP should not be performed if there is suspicion of raised ICP without first obtaining cranial CT or MRI.
•Should the CSF pressure be found to be very high (300mmCSF), even after relaxing the patient, and in the absence of idiopathic (benign) intracranial hypertension, manage as follows:
•Nurse the patient prone with no pillow.
•Start an infusion of 20% mannitol at 1g/kg over 20min.
•Start a neurological observation chart.
•Arrange an urgent CT of the brain and notify the neurosurgeons.
►►Do not instil saline into the subarachnoid space.
A ‘traumatic’ tap may cause a little local bleeding that is rarely of clinical significance. Patients with impaired clotting (remember warfarin) or platelet function are at risk of more extensive bleeding, and an LP should not be attempted unless the coagulopathy is corrected. An arachnoiditis, or spinal subdural, or epidural haemorrhage may develop. A spinal SDH is otherwise rare, and an intracranial SDH very rare.
•Glucose: ~ half to two-thirds of simultaneous blood glucose.
Note: if there is a traumatic ‘bloody’ tap, there may be hundreds or thousands of RBCs/mm3. If so, then white cells should be expected in the CSF, but in similar proportions to the peripheral blood.
•↑ by SOLs within the cranial vault such as oedema, masses, chronic inflammation.
•↑ by ↑ CVP, e.g. in the anxious patient with tensed abdominal muscles.
•↓ if the spinal subarachnoid space is obstructed, thus impeding CSF flow.
•Polymorphs (neutrophils): suggest acute bacterial infection.
•Lymphocytes and monocytes: viral and chronic infections or tumours.
•Eosinophils: tumours, parasites, foreign body reactions.
3.Glucose—↓ by non-viral processes causing meningeal inflammation.
4.Total protein—↑ by breakdown of the blood–brain barrier.
5.Igs specific to the CSF, i.e. without matching Igs in a simultaneous blood sample: inflammation within the theca, e.g. MS, infection, tissue damage.
These are shown in Table 9.1.
OHCM 10e, p. 822.
| Condition | Glucose | Protein | Cells | Comments |
| Acute bacterial meningitis | ↓ | ↑ | Often >300/mm3 | Polymorphs; lactate ↑ |
| Acute viral meningitis | N | N or ↑ | <300 mononuclear | Culture, antigen detection may be possible |
| Fungal meningitis | ↓ | ↑ | <300 mononuclear | Culture and antigen detection |
| Tuberculous meningitis | ↓ | ↑ | Mixed pleocytosis <300 | ZN stain organisms, culture PCR |
| Herpes simplex encephalitis | N | Mildly ↑ | 5–500 lymphocytes | PCR |
| GBS | N | ↑ | Normal | |
| SAH† | N | May be ↑ | Erythrocytes | Look for bilirubin pigments on spectrophotometry; xanthochromia unreliable |
| Malignant meningitis | ↓ | ↑ | Mononuclear | Rapid cytospin and look for malignant cells |
| HIV | N | N or ↑ | Mononuclear pleocytosis | Culture, antigen detection, antiviral antibodies |
| Neurosyphilis | N or ↓ | ↑ | <300 lymphocytes | VDRL |
| Neurosyphilis—early | ↑ | Treponema pallidum | ||
| Neurosyphilis—late | Immobilization tests |
† LP should be done >12h after onset of headache; the CSF should be spun down within 45min; ↓ numbers of RBCs in successive bottles are compatible with SAH.
Reprinted from Brain Res Bull, 61: 287–97 Kleine T Oet al. ‘New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF)’ (2003) with permission from Elsevier.
Davis A, Dobson R, Kaninia S, Giovannoni G, Schmierer K. Atraumatic needles for lumbar puncture: why haven’t neurologists changed? Pract Neurol 2016; 16: 18–22.
Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001; 345: 1727–33.
Thomas SR, Jamieson DR, Muir KW. Randomised controlled trial of atraumatic versus standard needles for diagnostic lumbar puncture. BMJ 2000; 321: 986–90.
Whiteley W, Al-Shahi R, Warlow CP, Zeidler M, Lueck CJ. CSF opening pressure: reference interval and the effect of body mass index. Neurology 2006; 67: 1690–1.
Usually more modern imaging techniques are much more informative, but there are occasions when these may not be speedily available. However, the plain SXR has quite low specificity and sensitivity for detecting many abnormalities of neurological importance.
•Pituitary fossa abnormalities.
•Bone changes related to meningiomata.
•Lateral view in the first instance.
•Specific views (e.g. orbits).
See Chapter 13.
•Shape and symmetry of the vault.
•Position of calcified pineal (midline shift?).
•Bone density changes (e.g. tumour, meningioma, Paget’s).
•Evidence of neurosurgical procedures.
(But see Computed tomography, pp. 598–600 for cranial CT; in general, CT is the preferred imaging modality.)
•Loss of consciousness or amnesia.
•Full-thickness scalp laceration.
If a skull fracture is detected, proceed to CT.
US may be used in a variety of modes.
•Doppler effect is used to assess alterations in the pattern (especially velocity) of flow in vessels.
•Duplex scanning combines B mode and Doppler.
•Can image from the clavicle (common carotid bifurcation) and internal and external carotids to the angle of the jaw.
•Can image the proximal and distal subclavian and vertebral arteries.
•Supraorbital artery (anterior circulation).
•Fibrofatty plaques and thrombus on plaques not very echogenic, therefore missable.
•Fibrous plaques more echogenic.
•Calcification in plaques is highly echogenic.
•Can sometimes detect intraplaque haemorrhage or ulceration.
Note: requires patient co-operation and considerable operator skill. High-grade stenosis can appear as total occlusion.
•Stenosis alters the normal pattern of velocities recorded.
•Combination of anatomic and flow imaging more sensitive and specific for clinically significant stenoses.
•Use of carotid US: most commonly in the assessment of patients with carotid territory ischaemic strokes or TIAs, who might be candidates for carotid endarterectomy. Such surgery should be performed as soon as possible, so carotid Doppler studies should be arranged promptly after the first event. If a patient has neurological signs or symptoms suggestive of posterior circulation events, there is little point in organizing carotid (i.e. anterior circulation) studies. Both the degree of stenosis and the morphology of the plaque (irregular plaques are more pathogenic) are important.
•Making, or excluding, the diagnosis of GCA can be difficult. Most guidelines suggest a temporal artery biopsy, but timely access to a biopsy may be difficult, GCA may occur without temporal artery involvement, and some patients with GCA have a −ve biopsy. Duplex studies of the temporal arteries have been shown to have high specificity and sensitivity.
•2MHz to penetrate thinner bone.
•Flow velocity in anterior, middle, and posterior cerebral, ophthalmic, and basilar arteries; carotid siphon.
•This is an area of active research, with new clinical indications being described frequently.
Croft AP, Thompson N, Duddy MJ, et al. Cranial ultrasound for the diagnosis of giant cell arteritis. A retrospective cohort study. J R Coll Physicians Edinb 2015; 45: 268–72.
Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: 107–16.
Tegeler CH. Ultrasound in cerebrovascular disease. In: JO Greenberg (ed.). Neuroimaging. New York: McGraw-Hill, 1995; pp. 577–95.
•Strongly suspected or confirmed SAH.
•Suspected cerebral vasculitis.
•Detection and delineation of other vascular abnormalities (e.g. AVM) of the brain or spinal cord.
•Delineation of tumour blood supply (occasionally).
1.Catheter passed via the femoral artery to the carotid or vertebral artery under image intensification.
3.In digital subtraction angiography (DSA), subtraction of pre- from post-contrast images (pixel by pixel) is used to help remove signals from bone density.
•Visualizes the aorta, major neck vessels, and sometimes the circle of Willis.
•Later images show venous system.
•Anteroposterior (AP), lateral, and oblique views—anterior and middle cerebral, and internal carotid arteries.
•Towne’s (half-axial) and lateral views—vertebral, basilar, posterior cerebral arteries.
•Occlusion, stenosis, plaques.
•Arteriovenous and other blood vessel abnormalities.
•Abnormal tumour circulation.*
•Displacement or compression of vessels.*
•Experimental role in acute stroke analysis.
Note: (*) although CT and MRI give finer spatial details, angiography is still useful, e.g. delineating blood supply of a tumour.
•Sensitivity to the contrast medium.
•Cerebral ischaemia, e.g. 2° to dislodgement of embolic fragments by catheter tip or thrombus in the catheter lumen.
•The rate of transient or permanent neurological defect following angiography depends on the operator.
Larsen DW, Teitelbaum GP. Radiological angiography. In: WG Bradley, RB Daroff, D Marsden, GM Fenichel (eds.). Neurology in Clinical Practice, 3rd edn. Boston: Butterworth-Heinemann, 2000; pp. 617–43.
Osborne AG.Diagnostic Cerebral Angiography, 2nd edn. New York: Lippincott, Williams & Wilkins, 1999.
•Largely superseded by CT and especially MRI.
•Still used in subjects in whom MRI is contraindicated (e.g. cardiac pacemaker, metallic implants, claustrophobia).
•Can screen whole spinal cord and cauda equina for compressive or expanding lesions.
•Spinal vasculature abnormalities.
A total of 5–25mL of (usually water-soluble) radio-opaque contrast medium is injected via an LP needle in the usual location (occasionally a cisternal puncture is used). By tipping the patient on a tilt table, the whole spinal subarachnoid space may be visualized.
•Spinal arachnoiditis (after months or years), now rare with water-soluble contrast.
•Acute deterioration if there is cord/root compression.
•Direct neurotoxicity (3 in 10,000):
•Allergic reaction to contrast. Give dexamethasone 4mg 12 and 2h prior to investigation if known allergy.
Note: send CSF for usual investigations ( Lumbar puncture, pp. 584–589).
Unstable positron-emitting isotopes (produced locally by a cyclotron or linear accelerator) are incorporated into biologically active compounds. The distribution of isotope shortly after IV administration is plotted. A range of compounds may be labelled such as ligands for specific neurotransmitter receptors or 18F-fluorodeoxyglucose (FDG). Commonly, PET is used to determine regional cerebral blood flow.
•Stable radioactive isotopes are incorporated into biologically active compounds.
•Their distribution after IV administration is plotted.
•These images often lack fine spatial detail.
Although the range of ligands available is limited, SPECT has certain advantages over PET:
•Isotopes are stable, and therefore a cyclotron or linear accelerator need not be on site.
•A labelled ligand can be given after a clinically important event, e.g. can give agent and scan within 20min of the occurrence of a seizure.
PET is not widely available as a clinical tool. With the ↑ availability of functional MRI (fMRI), the uses of PET in both clinical practice and neuroscience research have lessened. SPECT is more widely available in clinical centres.
PET is mainly used in neurological practice as whole-body FDG-PET to look for systemic malignancy, especially in paraneoplastic syndromes.
•An epileptogenic focus may show interictal hypometabolism (ictal hypermetabolism may be demonstrated with SPECT).
•Regional hypometabolism may be seen in neurodegenerative conditions such as Alzheimer’s disease and frontotemporal dementia. This may aid in diagnosis and differential diagnosis.
•‘Pseudo-dementia’ 2° to psychiatric disease such as depression (with normal SPECT scans) may sometimes be differentiated from dementia due to ‘organic’ neurological disease (with regional hypoperfusion), although psychiatric diseases may themselves be associated with regional hypoperfusion.
The functional integrity of the nigrostriatal system can be assessed, e.g. by the use of SPECT ligands for the dopamine transporter (e.g. FP-CIT). Such DAT scans can be used to differentiate true Parkinsonism from other causes of movement disorders.
•Determination of regional cerebral blood flow, glucose metabolism, and oxygen utilization
•Hypometabolism may be seen following a stroke. The affected area may exceed that with a demonstrable lesion on conventional CT or MR imaging.
•In vivo pharmacology (e.g. distribution of neurotransmitter receptors).
Positron emission tomography, pp. 894–897.
Marshall V, Grosset D. Role of dopamine transporter imaging in routine clinical practice. Mov Disord 2003; 18: 1415–23.
Younes-Mhenni S, Janier MF, Cinotti L, et al. FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127: 2331–8.
•Disturbances in the normal anatomy of the ventricular system.
•Width of cortical fissures/sulci.
•Areas of abnormal tissue density.
•Opacity or lucency of sinuses.
•In pineal/choroid plexus/basal ganglia, may be normal.
After administration of IV contrast medium, areas with a breakdown in the blood–brain barrier may ‘enhance’ (appear ‘white’). This may reveal previously ‘invisible’ lesions (isodense with the surrounding tissue). Especially useful for tumour and infection.
•Ring enhancement of tumours and abscesses.
•Solid enhancement of meningiomas.
•Meningeal enhancement with meningeal disease involvement.
Request a CT brain scan immediately for adult patients with any of the following risk factors:
•GCS score <13 on initial assessment in the emergency department.
•GCS <15 2h after the injury on assessment in the emergency department.
•Suspected open or depressed skull fracture.
•Any sign of basal skull fracture.
•One or more episodes of vomiting.
•Amnesia for events >30min before impact.
Request CT of the brain immediately for children with any one of the following risk factors:
•Age over 1 year: GCS <14 on assessment in the emergency department.
•Age under 1 year: GCS paediatric <15 on assessment in the emergency department.
•Age under 1 year and presence of bruise, swelling, or laceration (>5cm) on the head.
•Dangerous mechanism of injury.
•Clinical suspicion of non-accidental injury.
•Loss of consciousness lasting >5min (witnessed).
•Post-traumatic seizure but no history of epilepsy.
•Suspected open or depressed skull injury, or tense fontanelle.
•Any sign of basal skull fracture.
•Three or more discrete episodes of vomiting.
•Amnesia (antegrade or retrograde) lasting >5 min.1,2
CT, especially rapid image acquisition with helical CT, can allow imaging of the intracranial vasculature. CT angiography is particularly used in the detection of aneurysms and is ↑ widely available.3 CT venography is important in the assessment of possible intracerebral venous thrombosis.4
MRI is usually preferable, but plain CT can give information about the discs and bony architecture. CT may be helpful in suspected bony abnormalities. Some patients cannot have MRI because of, e.g. metallic implants. CT myelography can be used to demonstrate compressive lesions.
Plain radiograph is the initial investigation, but CT preferred when:
•GCS <13 on initial assessment.
•Technically inadequate plain radiographs.
•Clinical suspicion of injury despite normal radiograph.
•Patient being scanned for multi-region trauma.
•Strong clinical suspicion of injury despite normal radiograph.
•Technically inadequate plain radiographs.1,2
For most neurological indications, MRI is preferred to CT. It gives superior anatomical detail, and the range of sequences available allows superior determination of pathology. Unlike CT, there is no radiation exposure.
Note: MRI is not safe in the presence of ferromagnetic materials (e.g. certain prostheses, metal filings in the eye).
Some people find MRI difficult to tolerate because of claustrophobia. Counselling and experience of ‘dummy’ scanners prior to MRI may be helpful. Upright and ‘open’ scanners are increasingly available in specialist centres.
There is a variety of sequences available, which offer various advantages in delineating anatomy and pathology. This is an area of active research, with new sequences continuing to enter clinical practice. It is important that the requesting clinician provides appropriate clinical details, so that the radiologist may select the appropriate imaging sequences (and planes) to be used.
The commonest sequences are T1 and T2 (see Table 9.2).
•T1 CSF is hypointense (‘black’); fat and mature blood clot white.
•T2 CSF is hyperintense (‘white’).
Intravenously administered gadolinium leaks through areas of damaged blood–brain barrier to give a marked enhancement. It may be helpful in delineating:
•Tumour (may help differentiate from surrounding oedema).
MR may be used to obtain non-invasive images of blood vessels by using special MRI sequences and image reconstruction. Whilst standard angiography remains a ‘gold standard’ for many purposes, MRA has the advantage of being non-invasive and therefore ‘safe’. MRA images flow, rather than structure, and therefore may fail to ‘pick up’ low flow abnormalities such as cavernous angiomas. ►Caution: congenital abnormalities in the venous sinuses may be misinterpreted as thrombosis on MR venography (MRV).
•Assessment of patency of major arterial and venous vessels.
•Visualization of large (~3mm diameter) aneurysms.
Certain (indirect) indices of neural activity (most commonly changes reflecting regional perfusion) may be imaged with sufficient temporal and spatial resolution to be useful for both research and clinical applications (although fMRI has been largely a research tool to date). As a conventional MRI machine, albeit with special software, is required, fMRI is being ↑ used in the clinical setting.
•Demonstration of the language areas prior to epilepsy surgery.
•Demonstration of the functional anatomy of cognitive, sensory, and motor processes.
Table 9.2 Comparison of T1 and T2 MRI
| T1 | T2 | Tissue or lesion |
| Good anatomical detail | Reveals most pathology better than T1 | |
| Hypointense | Hyperintense | CSF |
| Hyperintense | Iso-intense | Fat, e.g. dermoid, lipoma, some metastases (melanoma), atheroma |
| Very hypointense | Very hyperintense | Cyst, hygroma |
| Hypointense | Hyperintense | Ischaemia, oedema, demyelination, many malignant tumours |
| Hyperintense | Moderately hyperintense | Subacute or chronic haemorrhage |
| Iso-intense | Hypointense | Acute haemorrhage |
| Iso-intense | Iso-intense | Meningioma |
Diffusion tensor imaging (DTI) allows anatomical tract tracing in vivo, using specialized software on standard MRI machines. As with fMRI, DTI was initially a research tool but has now entered clinical practice in some neuroscience centres. Major tracts, such as the corticospinal tract and the optic radiation, can be identified; these can then be spared during resective surgery.
Magnetic resonance spectroscopy (MRS) can be used to measure the concentration of certain neurochemicals in vivo (see Fig. 9.1). Because of the low concentrations of the neurochemicals, measurements are taken from large volumes of interest (typically several cm3), therefore giving MRS a much lower spatial resolution than standard structural MRI (spatial resolution typically of 1–2mm3). Metabolites commonly measured include the following (although it is often the ratio of different metabolites that is particularly useful):
•N-acetyl-aspartate (NAA) is present in high concentration in neuronEs and axons. Areas of neuronal or axonal loss show reduced levels of NAA.
•Choline (Cho) is associated with turnover in cell membranes and ↑ cell division. Areas of demyelination and malignant tumours can cause raised Cho. ↑ Cho can help distinguish recurrent tumours from post-radiotherapy changes (this can be a difficult distinction to make using standard MRI).
•Creatine (Cr) (and phosphocreatine) is a marker of metabolism. Reduced levels may indicate cell death.
•Myo-inositol (m-In) may be ↑ in certain diseases such as Alzheimer’s dementia.
•Lactate (Lac) is typically present in concentrations too low to be detected, except in areas of ischaemia, hypoxia, and certain tumours.
Fig. 9.1 The upper panels show the position of the volume of interest; the lower panel shows the MRS spectrum from that volume.
Faro SH, Mohamed FB (eds.). Functional Neuroradiology. New York: Springer, 2011.
Powell HW, Koepp MJ, Richardson MP, Symms MR, Thompson PJ, Duncan JS. The application of functional MRI of memory in temporal lobe epilepsy: a clinical review. Epilepsia 2004; 45: 855–63.
Stieltjes B, Brunner RM, Fritzsche K, Laun F.Diffusion Tensor Imaging: Introduction and Atlas. Berlin: Springer, 2013.
White PM, Teasdale EM, Wardlaw JM, Easton V. Intracranial aneurysm: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort. Radiology 2001; 219: 739–49.
Please give your neurophysiologists as much information as possible about your case and, if necessary, discuss it with them. They will then be in the position to organize the most appropriate neurophysiological investigations. In certain circumstances, you may need to specifically ask for unusual investigations such as repetitive stimulation in suspected LEMS ( Repetitive stimulation, p. 608).
•Orthodromic conduction velocity: electrically stimulates distal sensory branches (e.g. index finger) and records the evoked sensory nerve action potential (SNAP) proximally (e.g. over the median nerve at the wrist). The distance between the two sites (D) and the latency (L) of the onset of the SNAP determine the sensory conduction velocity (D/L). The SNAP amplitude is also useful.
•Antidromic conduction velocity: supramaximal electrical stimulation proximally; records distally (e.g. by a ring electrode on the little finger). By varying the position of the stimulating electrode, the conduction velocity in various portions of the nerve may be ascertained.
•↓ SNAP amplitude, or SNAP absence altogether, implies a lesion distal to the dorsal root ganglion.
•↓ velocity/↑ latency (see Table 9.3). Motor velocities are more commonly measured.
| Latency | Amplitude | |
| Median nerve (index finger to wrist) | 2–3ms | 9–40mV |
| Ulnar nerve (little finger to wrist) | 2–2.6ms | 6–30mV |
| Sural nerve (mid-calf to below med. mall) | 2–4ms | 5–40mV |
med. mall, medial malleolus.
Supramaximally stimulate a peripheral nerve trunk at a proximal (p) and a more distal (d) site. Record the time to the onset of the evoked muscle response (compound motor action potential (CMAP)) from each (Tp and Td) and the distance between them (D). The motor conduction velocity between p and d is therefore D/(Tp − Td).
•Median nerve in forearm (to abductor pollicis brevis) >48m/s.
•Ulnar nerve in forearm (to abductor digiti minimi) >48m/s.
•Common peroneal nerve (to extensor digitorum brevis) >40m/s.
(See Table 9.4.)
| Conduction velocity | AP amplitude | AP dispersion | |
| Axonal neuropathy | Late stage: ↓ distally > proximally (loss of fastest conducting axons) | Late stage: ↓ | Not seen |
| Demyelinating neuropathy | Marked slowing | Greater dispersion, perhaps especially in acquired, not inherited, demyelination | |
| Ganglionopathies | Slowing proportional to loss of large fibres; often not marked | ↓ proportional to loss of large fibres; often not marked | Not seen |
Note: limbs should be warm; look for asymmetries. What are your laboratory’s current values?
•Latency from stimulation of most distal site on nerve to CMAP.
•Median nerve (wrist to abductor pollicis brevis) <4.1m/s.
•Ulnar nerve (wrist to abductor digiti minimi) <3.8m/s.
•Radial nerve (spiral groove to brachioradialis) <5m/s.
Note: these latencies include time taken for impulses to pass along the most distal (unmyelinated) portion of the nerve and for transmission at the neuromuscular junction (therefore, they may not be used to calculate nerve conduction velocities). Compare with velocities elsewhere in the nerve being studied.
•Conditions in which the very distal segment of a nerve is compromised (most commonly carpal tunnel syndrome).
•Early demyelinating neuropathy (e.g. GBS).
•Chronic demyelinating neuropathy.
The waveform, amplitude, and area under the curve of the CMAP reflect the number of depolarized muscle fibres (e.g. reduced in axonal neuropathy and denervated muscle) and the temporal dispersion of conduction velocities in the motor neurones to them (e.g. ↑ in demyelinating neuropathy).
•If a motor nerve is stimulated, there are orthodromically directed action potentials (APs) that may cause a response in the muscle (CMAP). However, antidromically directed APs will also pass proximally towards the cell body. If these result in sufficient depolarization of the axon hillock, then a second orthodromic volley will pass down the nerve. This may cause a second motor AP (the F wave). Therefore, the F wave: (i) does not involve synapses (other than the neuromuscular junction, of course) and (ii) depends on the integrity of the whole axon.
•It may be difficult to elicit.
•Delay or absence of the F wave may reflect a lesion proximal to the site of stimulation, in parts of the nerve that may be inaccessible to electrodes, e.g. brachial plexopathy or thoracic outlet syndrome. May also be an early feature in GBS.
•This is ‘an electrical ankle jerk’: submaximal stimulation of the posterior tibial nerve in the popliteal fossa causes trans-synaptic activation of the soleus, recorded as a CMAP.
•Amplitude may be ↓ by afferent or efferent problems, e.g. neuropathy or radiculopathy.
•Procedure: stimulate a motor nerve with 3–5 supramaximal stimuli at 2–4Hz, whilst recording evoked CMAPs.
•Normal response: no change in CMAP amplitude.
•In MG: >10% decrement in CMAP amplitude after two stimuli.
•After voluntary contraction or after rapid stimulation (20–50Hz) for 2–10s, the CMAP amplitude, often initially small, ↑ by 25% (suggestive) or 100% (diagnostic).
•At a slow (3Hz) rate of stimulation, there is a response decrement.
•A concentric needle electrode is usually used.
•It is inserted into the muscle to be studied.
•The difference in potential between the inner part of the electrode and the outer core is amplified and displayed on an oscilloscope or computer screen.
•It is also ‘displayed’ as an auditory signal, and experienced electromyographers as much listen to as watch the pattern of electrical activity.
Normal muscle is ‘silent’ (electrically inactive) at rest (there is no ‘spontaneous activity’), although there will be a brief burst of activity when the electrode is first inserted (the ‘insertional activity’).
The electrode can pick up electrical activity from muscle fibres within about 0.5mm of its tip; therefore, muscle fibres from several motor units (each innervated by a different motor neurone) in this volume can contribute to the signal. However, with care, potentials from a single motor unit may be recorded when a co-operative subject tries to exert the muscle a little (the ‘motor unit potential’). With ↑ muscular effort, more muscle fibres are recruited, giving rise to the ‘interference pattern’.
5.In addition, certain other patterns may be observed in certain diseases (in particular, myotonia).
•Usually there is a brief burst of potentials which lasts <1s.
•Insertional activity is normal in upper motor neurone (UMN) lesions and most non-inflammatory myopathies.
•It may be longer-lasting in lower motor neurone (LMN) lesions, inflammatory myopathies, and acid maltase deficiency.
•In myotonia, myotonic discharges occur ( Electromyogram, p. 611).
•Normal muscles at rest are silent.
•This is also the case in UMN lesions, non-inflammatory myopathies (unless 2° denervation has set in), and myotonia.
•Fibrillation potentials and +ve sharp waves are seen in LMN lesions and inflammatory myopathies. They occur in regular bursts of constant amplitude (unlike activity related to voluntary contraction).
•Fibrillation potentials are spontaneous APs in irritable, acutely denervated muscle fibres. They are low-amplitude, brief −ve potentials.
•Positive sharp waves are brief +ve potentials, followed by a −ve wave. Typically, they can be seen for 2–3 weeks after denervation but may persist.
•If the electrode is positioned quite close to the fibres of a motor unit which is active during slight voluntary contraction, then a motor unit potential (MUP) may be recorded. In normal muscle (and in UMN lesions), this waveform is triphasic, 5–10ms, and has an amplitude of 0.5–1mV (larger muscles have larger motor units).
•In myopathies and muscular dystrophies, the motor units are smaller and polyphasic. They tend to be briefer but, in some cases, last longer than usual.
•In denervated and then reinnervated muscles (typically LMN lesions), the size of individual motor units ↑ (as the surviving motor neurones ‘take over’ the muscle fibres previously innervated by the now absent other motor neurones). MUPs therefore are of greater amplitude and duration and are polyphasic.
•In myotonia, myotonic discharges are seen.
Note: up to 15–20% of MUPs in ‘normal’ muscle may be polyphasic.
•Normally, as the strength of voluntary contraction ↑, ↑ numbers of motor units are recruited, and these units tend to be larger (Heinneman’s size principle). The potentials due to these active units overlap and become difficult, and finally impossible, to tell apart—a full ‘interference pattern’, usually well below the maximum voluntary contraction.
•In muscle diseases, a full interference pattern may be produced, but it is of low amplitude. In weak muscles, there may be ‘early recruitment’ (i.e. recruitment of many motor units at low levels of voluntary contraction).
•In denervated muscles, a full interference pattern may not be achieved, because of the ↓ number of motor units.
•In UNM lesions, there is a lower frequency of ‘normal’ MUPs.
•High-frequency repetitive discharges occurring after voluntary movement or provoked by moving the electrode. The amplitude and frequency wax and wane, giving the auditory signature likened to the sound of a Second World War dive bomber (or a motorcycle).
•Note: following the onset of a neuropathy, it may take at least 10–14 days for evidence of denervation to appear in the EMG. Therefore, a repeat study after this time is often useful.
A recording electrode with a smaller recording surface than usually used samples a few muscle fibres from a single motor unit (supplied by a single motor neurone). The variability (‘jitter’) in the timing of APs from different muscles should be <20–25ms. Conduction block during voluntary contraction may also be shown. These techniques are used to investigate neuromuscular disorders and reinnervation in neuropathies.
Blum AS, Rutkove SB (eds.). The Clinical Neurophysiology Primer. Totowa: Humana Press, 2007.
The standard EEG is non-invasive. Electrodes are attached to the scalp with collodion adhesive. Stable recordings may be made for days. Usually they are arranged according to the international 10–20 system. This is a method for positioning electrodes over the scalp in an orderly and reproducible fashion. Additional electrodes can be applied to the scalp, depending on the region of interest.
•Hyperventilation for 3–5min can activate generalized epileptiform changes (and precipitate absence seizures):
•Can ↑ frequency of focal discharge.
•Can ↑ slow-wave abnormalities.
•Photic stimulation (a strobe light at 30cm with a frequency of 1–50Hz); this can produce several patterns of activity:
•Photoparoxysmal response—bilateral spike or spike and wave discharges not time-locked to the visual stimulus, which may outlast the visual stimulus by hundreds of milliseconds. Generalized, but may have frontal or occipital predominance; commonly seen in idiopathic generalized epilepsies; high-voltage occipital spikes, time-locked to the stimulus; weakly associated with epilepsy.
•Photomyogenic (photomyoclonic) responses—non-specific, mostly frontal spikes due to muscle activity; associated with alcohol and some other drug withdrawal states.
•Subject either stays awake the night before the recording or is given a small dose of choral prior to the recording (sometimes both).
•Subjects tend to show the earlier stages of non-REM sleep.
•These studies ↑ the yield of EEG abnormalities, including epileptiform ones.
•By capture of ‘natural sleep’: certain seizure types are commoner in sleep (e.g. juvenile myoclonic epilepsy (JME)).
•Sleep deprivation itself ↑ the number of seizures and epileptiform changes.
Polysomnography, p. 621.
| Activity | Frequency (Hz) | Amplitude (mV) | Scalp location | Behavioural state |
| Alpha | 8–12 | 20–60 | Usually occipital | Maximum relaxed, awake, eyes closed |
| Beta | >13 | 10–20 | Frontocentral | Wakeful, drowsy; REM and SWS 1 and 2 |
| Theta | 4–8 | Variable diffuse | Frontocentral, temporal | Minimally awake, drowsy, SWS |
| Delta | <4 | Variable | Diffuse | Awake; drowsy |
| Mu | 8–10 | 20–60 | Central | Awake, suppressed in voluntary movements |
SWS, slow-wave sleep.
The terms alpha, beta, theta, and delta are often used to describe the background activity but are also used to describe the frequency of EEG activity.
Sharp activity may be a normal phenomenon.
There is a wide range of normal EEG phenomena. Some of the common patterns in the awake adult are listed in Table 9.5.
•A variety of EEG abnormalities may be seen outside the peri- or per-seizure period.
•Abnormalities in the EEG are not restricted to the appearance of abnormal waveforms.
•The loss, or redistribution in the scalp location, of normal background activities is abnormal.
1.General excess of slow waves—commonly seen in:
2.Focal slow waves—commonly seen in:
•Large cerebral lesions (e.g. tumour, haematoma).
3.Localized, intermittent, rhythmic slow waves—may be seen in idiopathic generalized and localization-related epilepsies.
•Spikes (if last <80ms) or sharp waves (80–200ms) may be associated with slow waves.
•Consistently focal spikes suggest epilepsy with a focal seizure onset.
Note: 2–4% of non-epileptics have occasional spikes or sharps.
EEG patterns may show periodicity. These patterns may be epileptiform or not, and may be focal or generalized. They are an abnormal EEG feature, the interpretation of which depends on the clinical context.
•Burst suppression: bursts of generalized high-voltage mixed waveforms, alternating with generalized voltage suppression:
•Late-stage status epilepticus (both convulsive and non-convulsive).
•Triphasic waves over one or both temporal lobes: common in herpes simplex encephalitis.
•Periodic lateralized epileptiform discharges (PLEDs) are localized sharp or slow-wave complexes 0.2–1s long, every 1–5s:
•Non-specific but suggest localized cerebral insult (stroke, haematoma, tumour).
•Occasionally seen in migraine and focal epilepsies.
•BIPLEDs are bihemispheric PLEDs: suggest more widespread insults, e.g. anoxia, encephalitis.
•Bilateral or generalized high-voltage complexes for 0.5–2s every 4–15s: characteristic of subacute sclerosing panencephalitis (SSPE).
•Not seen in vCJD (may see a ‘disorganized’ EEG without repetitive complexes).
•Runs of broad triphasic waves (1.5–3Hz): severe metabolic encephalopathy (e.g. renal or hepatic failure).
•Periodic spikes or sharp waves: bi- or multiphasic morphology (0.5–2Hz); usually generalized—suggest severe encephalopathy, e.g.
•CJD (in the setting of rapid dementia and myoclonus).
•Tricyclic antidepressant overdose.
•Generalized, bilaterally synchronous epileptiform discharges with virtually normal background.
•Absence epilepsy: 3Hz spike and wave.
•JME: 6Hz multiple spike and wave.
•Inter-ictal background activity: excess slow.
•Inter-ictal epileptiform activity: irregular spikes or sharp and slow waves 1.5–4Hz. Usually generalized, but may show asymmetry or (multi-) focal features.
•Inter-ictal EEG is often normal, particularly if the focus is located deeply (especially common with frontal foci).
•There may be lateralized or localized spikes or sharp waves.
•Routine EEG with photic stimulation and hyperventilation gives about up to a 50% detection rate for inter-ictal epileptiform abnormalities in a subject with epilepsy (higher ‘yield’ in 1° generalized epilepsies than in localization-related epilepsies).
•Sleep-deprived or choral-induced sleep recording may ↑ the yield of EEG abnormalities to up to 60–70%.
•Consider 24h or longer ambulatory EEG, ideally with audio/video monitoring. Most useful in helping to determine the nature of the seizure in a subject with frequent (e.g. daily) attacks.
In general, avoid reduction in anti-epileptic drugs or drugs such as pentylenetetrazole to induce seizures, except in exceptional circumstances, e.g. videotelemetry as part of work-up for epilepsy surgery.
Note:
•No inter-ictal spikes does not imply no epilepsy.
•Similarly, inter-ictal spikes do not always imply epilepsy.
•A −ve ictal EEG does not necessarily imply a non-epileptic (‘pseudo-’) seizure, especially in simple partial and some brief complex partial seizures (CPS). Scalp electrodes may fail to record deep, especially frontal, activity.
•However, a tonic–clonic seizure with loss of consciousness should be associated with an epileptiform EEG during the ictus. This EEG activity may be obscured by muscle artefact, but post-ictal slowing may be seen.
•The EEG may be slow after a tonic–clonic seizure for many tens of minutes.
Note: the diagnosis of epilepsy is mainly clinical! Remember that most episodes of altered consciousness are not epileptic in origin. In many cases, cardiological investigations are appropriate. Have a low threshold for ordering a 12-lead ECG. Ambulatory ECG monitoring, particularly with cardiac memo devices, and ambulatory BP monitoring can be very useful.
•Classification (e.g. CPS vs absence).
•Assessment of frequency of seizures (e.g. ambulatory EEG to assess frequency of absence seizures).
•Reduction in inter-ictal discharges in some syndromes (e.g. absence, photosensitive epilepsy) correlates with anti-epileptic drug efficacy.
Often not particularly helpful. Modern imaging studies usually provide more information.
•Small, deep, or slow-growing lesions often cause no effects.
•Asymmetric voltage attenuation may be caused by a subdural haematoma (or other fluid collection) overlying the cortex.
•Direct grey matter involvement may cause alteration/loss of normal EEG or cause epileptiform discharges.
•Subcortical white matter changes can cause localized polymorphic slow waves.
•Deeper subcortical lesions tend to produce more widespread slow-wave disturbances.
•CJD and SSPE have relatively characteristic EEG associations.
•Meningitis and encephalitis cases may show diffuse background disturbances and polymorphic or bilateral intermittent slow wave abnormalities.
•Encephalitis usually causes more changes than meningitis.
•Focal changes may be seen over abscesses and in cases of herpes simplex encephalitis.
•To exclude some conditions such as toxic encephalopathy, non-convulsive status epilepticus (NCSE).
•A few dementing conditions have characteristic EEGs (CJD, SSPE).
•Slowing of background frequency occurs in Alzheimer’s disease, but values may overlap with those of the normal aged, therefore not very helpful clinically.
•Helpful in diagnosing NCSE (absence and complex partial status).
•To exclude cerebral dysfunction.
•Not very useful in psychiatric diagnosis per se, but an abnormal EEG in a confusional state may help exclude psychogenic causes for an apparent reduction in level of consciousness.
•Diffuse slowing in mild cases.
•Other abnormalities may develop in later stages.
•Specific patterns may be seen in certain aetiologies.
•Excess fast activity: barbiturate and benzodiazepine toxicity.
•Triphasic waves: hepatic and renal failure, anoxia, hypoglycaemia, hyperosmolality, lithium toxicity.
•Periodic spikes or sharp waves: anoxia, renal failure, lithium and tricyclic antidepressant toxicity.
•EEG, especially serial EEGs, provides an indication of the degree of cerebral dysfunction.
•In general, any ‘normal’-looking EEG, spontaneous variability, sleep–wake changes, and reaction to external stimuli are relatively good prognostic signs.
•An invariant, unreactive EEG is a poor prognostic sign; the pattern, however, is not uniform; it may include periodic spikes of sharp waves, episodic voltage attenuation, alpha coma, and burst suppression.
•May give some diagnostic clues, e.g. localized abnormality—supratentorial mass lesion; persistent epileptiform discharges—status epilepticus.
•‘Alpha coma’: monotonous unresponsive alpha with anterior distribution seen after a cardio/respiratory arrest is a poor prognostic feature.
•Monotonous, but partially reactive, alpha may follow brainstem infarcts.
These are generally restricted to specialist centres, most commonly used in the pre-surgical work-up of patients.
Foramen ovale electrodes, corticography (usually done by laying strips of electrodes on the surface of the brain), and depth EEG (electrodes implanted into the parenchyma of the brain) may be used, depending on the region of interest. Sphenoidal electrodes are rarely used today but can give useful EEG information about the medial temporal structures.
Blum AS, Rutkove SB (eds.). The Clinical Neurophysiology Primer. Totowa: Humana Press, 2007.
National Institute for Health and Care Excellence (2012). Epilepsies: diagnosis and management. Clinical guideline CG137. 
https://www.nice.org.uk/guidance/cg137.
•This is a multimodal recording used in the analysis of sleep-related disorders.
•There is concurrent recording of EMG, EEG, and electro-oculography (EOG—eye movements), often with audiovisual channels. Other physiological parameters may also be recorded, e.g. nasal airflow, chest expansion.
Sleep is divided into three stages (N1–N3) of progressively ‘deeper’ non-REM (NREM) sleep and a stage of REM sleep (see Table 9.6), characterized physiologically by bursts of rapid eye movements (saccades). NREM sleep was previously divided into four stages: 1 (now N1), 2 (now N2), and 3 and 4 (now N3).
| Stage | Behaviour | Main EEG pattern | Comments |
| N1 | Drowsy | Diffuse alpha and theta | Diminished EMG; rolling eye movement |
| N2 | Light sleep | High theta; K complexes; sleep spindles | Further diminished EMG; may have rolling eye movements |
| N3 | Deep sleep | Delta | Diminished EMG; no eye movements |
| REM | No body movements, but vivid dreams | Low amplitude, mixed frequency | Muscular atonia; rapid eye movements |
REM: rapid eye movements.
There is progression through stages N1-N3, and several episodes of REM during a typical night’s sleep. Polysomnography can be important in understanding the pathophysiology of the insomnias, parasomnias and other sleep patterns.
This is a diagnostic test for narcolepsy. Following a good night’s sleep, normal subjects typically enter REM sleep with a latency of >>10min (usually ~90min). In narcolepsy, the latency is <10min.
Abad VC, Guilleminault C. Polysomnographic evaluation of sleep disorders. In: MJ Aminoff (ed.). Aminoff’s Electrodiagnosis in Clinical Neurology, 6th edn. Oxford: Elsevier Saunders, 2012; p. 727.
Whilst many techniques and protocols have been developed in research laboratories, there are only a few techniques in widespread clinical use. A stimulus is delivered to the periphery, thus activating a sensory system and evoking an electrical response over a more central, often cortical, area. Multiple surface electrode recordings time-locked to the peripheral stimulus are recorded and averaged, to help eliminate ongoing random background ‘noise’ from the sensory stimulus-evoked ‘signal’. Deviations of this evoked potential (EP) or response (ER) from the norm (especially in latency and waveform) suggest pathology in the sensory pathway tested.
An alternating chequerboard pattern (temporal frequency 1–2Hz) is presented to each eye individually (see Fig. 9.2). The EP is recorded over the occipital (1° visual) cortex. Most commonly, the first large +ve wave, called P1 or P100 (as it typically occurs at about 100ms), is studied.
A delayed, smaller, or dispersed VEP indicates disease in the retino-geniculo-striate pathway (if severe refractive errors or cataracts have been excluded), but most commonly affecting the optic nerve (a uniocular deficit implies a lesion anterior to the optic chiasm) or at the chiasm.
In subjects with very poor vision or fixation and in the very young, a bright flash may be used as the stimulus. This gives less reproducible results, particularly in the P100 latency.
The VEP is used in general to document intrinsic, inflammatory, or compressive lesions of the optic nerve (or chiasm).
1.Suspected optic or retrobulbar neuritis.
2.In a patient with suspected MS, evidence of a VEP abnormality in an asymptomatic eye would suggest a previous episode of optic neuritis.
3.Evaluation of hysterical blindness (may need to use a strobe light stimulus if patient non-co-operative).
4.Evaluation of optic nerve function in compressive lesions such as dysthyroid eye disease, optic nerve glioma.
5.Follow-up after surgery to decompress the optic nerve or chiasm.
6.Assessment of poor visual acuity in patients unable to co-operate with usual testing. Vary the size of the chequerboard squares; subjects with poor acuity will only have a VEP to the coarser patterns.
•Stimulation site over a peripheral nerve, e.g. ulnar or median at the wrist, common peroneal at the knee, posterior tibial at the ankle (see Fig. 9.3).
•Record over Erb’s point (above the medial end of the clavicle), C7 or C2 vertebra, or the parietal cortex for arm stimulation; L1, C7, C2, or vertex for leg stimulation.
•Calculate absolute and interpeak latencies.
•Need to show with NCS that distal parts of the somatosensory pathways are conducting normally.
•Assesses the dorsal column, not anterolateral (spinothalamic) tract pathways:
•For example, stimulate the median nerve at the wrist; prolonged latency to Erb’s point suggests a brachial plexus (or more distal) lesion.
•Prolonged Erb’s point to C2 latency suggests a spinal cord lesion.
•Evaluation of subclinical myelopathy in possible MS.
•Evaluation of hysterical sensory loss.
•Per-operative monitoring (e.g. during scoliosis surgery).
(See Fig. 9.4.)
•Stimulus: rarefaction clicks of 50 or 100ms duration, presented mono-aurally at 10Hz at 60–70dB above threshold (masking the noise to the other ear).
•Record over the mastoid and vertex of the skull.
•Classic waveform has seven peaks, said to be generated by sequential auditory nuclei:
•I: VIIIth nerve (must be present to interpret subsequent waves).
•II: cochlear nucleus (may be absent in normals).
•IV: lateral lemniscus (may be absent in normals).
•V: inferior colliculus (should be 50% or more of wave I’s amplitude).
•VI: medial geniculate (too variable for regular clinical use).
•VII: auditory thalamocortical radiation (too variable for regular clinical use).
Latency I–V (central conduction time) should be no more than 4.75ms. The difference between left and right central conduction times should be <0.4ms.
•Hearing assessment, especially in children.
•Evaluation in suspected MS and other myelinopathies (e.g. adrenoleukodystrophy; MRI more important now).
•Evaluation and detection of posterior fossa lesions (e.g. acoustic neuromas; MRI more important now).
•Evaluation of brainstem function (e.g. tumour, CVAs).
•Evaluation of brainstem function in coma and brain death.
•Per-operative, e.g. acoustic neuroma excision.
Traditionally, trimodal EPs (VEPs, SSEPs, and BAEPs) have been requested to look for evidence of a disturbed conduction in multiple sensory systems. Modern practice, however, is to request only VEPs, if any at all. MRI is much more useful in demonstrated dissemination of CNS lesions.5
Blum AS, Rutkove SB (eds.). The clinical neurophysiology primer. Totowa: Humana Press, 2007.
•Brief, high-current pulse produced in a circular or figure-of-eight-shaped coil held over the scalp.
•This induces a magnetic field with flux perpendicular to the coil.
•This, in turn, produces an electric field perpendicular to the magnetic field.
The result is excitation or inhibition of the subjacent cortex (depending on stimulus parameters).
•Transcranial magnetic stimulation (TMS) has been used for diagnostic purposes in a number of ways, although as yet it is not in widespread clinical use.
•TMS over the motor cortex indirectly (presumably via synaptic activation of corticospinal neurones) causes a volley of activity in the corticospinal tracts. The latency of the EMG in, say, the abductor digiti minimi may be measured.
•May be used in cervical myelopathy and MS to show ↑ latency of EMG in hand muscles evoked by TMS over the motor cortex. If the EMG latency to more distal stimulation (e.g. at C7 over the spinal cord and in the ulnar nerve) is normal, then an ↑ central motor conduction time may be inferred.
•Latency may also be ↑ in other neurodegenerative conditions.
Abnormalities in the amplitude of motor evoked potentials (MEP) may reflect abnormalities anywhere in the pathway from the motor cortex to the muscles.
•If a subject maintains muscle contraction and a single suprathreshold TMS pulse is applied to the contralateral motor cortex, ongoing EMG activity ceases for a few hundred milliseconds after the MEP (the ‘silent period’).
•Silent period may be long in, e.g. stroke, MS, spinal cord injury.
•Silent period may be short in, e.g. MND, PD.
•Interhemispheric inhibition may be ↓ in MS or MND.
•It may be absent following lesions to the corpus callosum.
•High thresholds may be seen in stroke or MS.
•Low thresholds and ↑ intracortical inhibition may be seen in MND.
•↓ intracortical inhibition may be seen in PD.
Some authorities have used TMS to evoke muscle activity in ‘paralysed’ limbs in patients with psychogenic paralysis. This needs to be done in the context of a ‘holistic’ approach to the patient, aimed at dealing with any psychological pathology.
There have been many TMS studies, some that may prove useful as clinical tests, e.g.
•Determination of lateralization of language function by repetitive TMS (rTMS) prior to surgery for epilepsy.
•Assessment of cortical excitability in certain epilepsy syndromes.
•Assessment of ↓ intracortical inhibition in dystonia.
•Assessment of recovery from stroke.6
Currà A, Modugno N, Inghilleri M, Manfredi M, Hallett M, Berardelli A. Transcranial magnetic stimulation techniques in clinical investigation. Neurology 2002; 59: 1851–9.
Kobayashi M, Pascuel-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol 2003; 2: 145–56.
•Of pelvic floor muscles may be helpful in faecal incontinence, stress urinary incontinence, and cauda equina syndrome.
•Pelvic floor and sphincter muscle EMGs may reflect pudendal nerve damage.
•Anal sphincter EMG abnormalities may reflect damage to Onuf’s nucleus, e.g. in multi-system atrophy. It is characteristically unaffected in MND.
•In suspected sacral spinal cord, conus medullaris, and equina lesions.
•Measurement of rate and amount of urine flow over time.
•Allows calculation of parameters such as time to maximal flow, maximum and mean flow rate, and volume voided.
•Post-micturition US can determine residual volume.
•Measurement of intravesicular pressure during filling (usually at 50mL/min) or emptying. Typically, bladder filling sensation starts at about 100mL and the bladder is full at 400–600mL (with no more than 15cmH2O rise in pressure). Detrusor instability may cause sharp rises in pressure during filling.
•During voiding, flow rate should be >15mL/min (♂) or >20mL/min (♀) with pressures of <50cmH2O (♂) or 30cmH2O (♀).
Fowler CJ. Investigational techniques. Eur Urol 1998; 34(Suppl): 10–12.
Panicker JN, Fowler CJ. The bare essentials: uro-neurology. Pract Neurol 2010; 10: 178–85.
•Explain the test to the patient.
•Select weak and/or fatiguable muscles to be assessed.
•Draw up 0.6mg of atropine (for use if extreme bradycardia develops), 10mg of edrophonium in 5mL of normal saline (A), 5mL of normal saline (B), and saline flush.
•Administer 1mL of the test solution (A or B, ideally patient and administrating physician should be blinded to the nature of the solution).
•If no adverse reaction, administer the remaining 4mL.
•Repeat with the other solution (B or A).
Note: if the diagnosis of MG is clinically obvious, and the patient has responded to pyridostigmine given empirically, there is little point in stopping this and performing an edrophonium test.
•In MG, there should be a response within 30–60s, which should wear off in 2–4min.
•There may be a response in LEMS, polymyositis, and MND.
Amobarbital is injected into the right or left internal carotid artery. It is a short-acting barbiturate that temporarily causes hemispheric dysfunction on the injected side. If injected into the left in most right-handers, the ability to speak and continue to hold up the right arm is temporally impaired. If speech is preserved following right-sided injection, it suggests normal left lateralization for language function. More complex testing may also be undertaken during the period of hemispheric dysfunction, but it is usually used to determine language dominance prior to certain neurosurgical procedures. Increasingly, non-invasive techniques, such as fMRI, are being used in place of the Wada test.
Wagner K, Hader C, Metternich B, Buschmann F, Schwarzwald R, Schulze-Bonhage A. Who needs a Wada test? Present clinical indications for amobarbital procedures. J Neurol Neurosurg Psychiatry 2012; 83: 503–9.
•Always liaise with those taking the biopsy and those processing it!
•A biopsy should be undertaken to answer specific questions, in light of a differential diagnosis formulated following history, examination, and other investigations.
•1° muscle disease, e.g. metabolic myopathy, polymyositis, muscular dystrophy.
•Mitochondrial cytopathies (even in the absence of clinical muscle involvement).
•Multi-organ disease, e.g. vasculitides.
•An involved, but not end-stage, muscle.
•One that has not been used for EMG recording or had an injection for >1 month.
•Quadriceps and deltoid often used.
•Can fix specimen at in situ length.
•Especially for inflammatory myopathy and in vasculitis.
•Difficulties in orientating the sample.
•Examination of small blood vessels.
•Distinction between segmental demyelination and axonal degeneration (if not already determined).
•Certain neuropathies with characteristic histological features, e.g. due to amyloid deposition, sarcoid, vasculitis, neoplastic involvement.
•Certain myelinopathies (e.g. leukodystrophies) with peripheral nervous system (PNS) and CNS involvement.
•The cutaneous branch of the sural nerve at the ankle (usually).
•Superficial peroneal (sometimes).
•Superficial radial (occasionally).
•Occasionally, small motor nerve twigs are obtained in muscle biopsy.
•Overlying skin may be co-biopsied.
•2–3cm of full-thickness nerve or fascicle.
•Routine light microscopy (morphometry, structural survey; amyloidosis).
•Frozen section light microscopy (immunochemistry).
•Teased out single fibres (to examine sequential myelin internodes).
•Diagnosis and management of suspected 1° and some metastatic brain tumours.
•Differential diagnosis of other mass lesions (inflammatory and infective).
•Differentiation of radiation necrosis and tumour regrowth.
•Differentiation of neoplastic and non-neoplastic cysts (and their drainage).
•Diagnostic biopsy of a suspected infectious lesion that has not responded to a trial of therapy.
•Diagnosis of cerebral vasculitis or vasculopathy.
•High-quality cranial CT/MRI, possibly with contrast, to delineate the lesion.
•If no discrete lesion, generally an area of non-dominant, non-eloquent cerebrum is taken.
•Stereotactic needle biopsy with image guidance:
•Deep, small lesions in ‘eloquent’ areas.
•Multiple biopsies along the needle track (useful in heterogeneous lesions such as some gliomas).
•When resection considered during procedure.
•Intra-operative evaluation of frozen samples:
•For example, can a biopsy be made?
•For example, is the sample adequate?
Note: caution in suspected CJD!!
•Haematological and other malignancies.
•Most neuronal storage diseases affect the autonomic nervous system, so evidence can be sought in neurones of the gut’s intrinsic plexi.
•Electrophoresis of serum and CSF separates protein components by size and charge.
•OCBs may be present in serum and CSF. Bands in the CSF not seen in the serum suggest intrathecal-specific synthesis of Igs.
•This pattern is seen in most (95%) cases of established MS but may also occur in other conditions such as chronic meningitis, neurosyphilis, SSPE, and neurosarcoid (although uncommonly).
Thompson EJ. Cerebrospinal fluid. In: RAC Hughes (ed.). Neurological Investigations. London: BMJ Publications, 1997; pp. 443–66.
PNS and CNS are affected in many multi-system disorders; markers in blood and other fluids and tissues for these are therefore commonly requested in neurology patients.
•Gliadin and endomysial antibodies in coeliac disease.
•Serology for many diseases, e.g. Borrelia in Lyme disease, HIV.
•Screening for the Leiden mutation in factor V.
•carcinoembryonic antigen (CEA) for gut neoplasia.
•Serum and urinary paraproteins in haematological disorders like myeloma.
•TSH, FT4, and FT3, thyroid autoantibodies in thyroid dysfunction.
•Wilson’s disease: blood copper and caeruloplasmin; some authorities also request 24h urinary copper excretion. Note: slit lamp examination performed by an experienced ophthalmologist reveals Kayser–Fleischer rings in most cases of Wilson’s disease with neurological involvement.
•Phaeochromocytoma: catecholamine metabolites in three 24h urine collections.
•MG: anti-ACh receptor and muscle-specific kinase (MuSK) antibodies.
•Neuromyelitis optica: aquaporin 4 and MOG antibodies
Certain neurological syndromes are ‘paraneoplastic’, i.e. due to remote, but non-metastatic, effects of non-nervous system cancers. These paraneoplastic syndromes are rare, but important to recognize. In perhaps 50% of cases, the neurological symptoms may predate those of the cancer. This is an area of intensive research. Antibody tests that are well described include those in Table 9.7.
Table 9.7 Paraneoplastic antibodies
| Antibody | Paraneoplastic syndrome | Associated tumour |
| Anti-Hu (ANNA1) | Small-cell lung cancer (SCLC) | |
| Anti-Yo (PCA1) | Cerebellar degeneration | Breast, ovary |
| Anti-Ri (ANNA2) | Brainstem encephalitis | Breast, SCLC |
| CV2 (CRMP5) | Thymoma, SCLC | |
| Anti-Ma2 (Ta) | Testis, lung | |
| Anti-amphiphysin | Breast, SCLC | |
| CAR | Retinopathy | Breast, SCLC |
| Tr | Cerebellar ataxia | Hodgkin’s |
Most of these paraneoplastic antibodies target intracellular antigens and are not thought to be pathogenic in themselves. Increasingly, autoantibodies to antigens on the surface of neurones or glia are being recognized and associated with clinical syndromes (see Table 9.8). Such antibodies may be directly pathogenic. Recognizing clinical syndromes associated with these cell surface-directed antibodies is important, as many respond to immunotherapies.
Table 9.8 Neuronal surface antibody antibodies
| Antibody | Syndrome | Associated tumour |
| NMDAR | Encephalitis; dyskinesia; psychiatric presentation; epilepsy | Ovarian teratoma |
| LGI1 | Limbic encephalitis | Rare |
| CASPR2 | Lung, breast, thymus | |
| GABABR | SCLC | |
| mGluR5 | Hodgkin’s lymphoma | |
| GlyR | Progressive encephalomyelitis with rigidity and myoclonus | Thymoma |
| VGCC | Cerebellar ataxia | SCLC |
| mGluR1 | Cerebellar ataxia | Hodgkin’s lymphoma |
Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr Opin Neurol 2012; 25: 795–801.
Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiat 2004; 75: 1135–40.
Honnorat J, Antoine J-C. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2007; 2: 22.
Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012; 83: 638–45.
Many ‘inborn errors of metabolism’ cause neurological disease. A variety of investigations, including tests on blood, urine, and CSF, biopsies, and genetic analyses, are used in their diagnosis ( Diagnostic and prognostic antibodies, and other markers in blood and urine, pp. 636–638; Genetic tests, pp. 642–645; for an accessible review, see Gray et al.).7
Many autosomal recessive and X-linked metabolic diseases are caused by reduced or absent activity of a specific enzyme, in turn due to a single gene defect.
For example, McArdle’s (glycogen storage disease V) demonstrates the absence of phosphorylase activity in muscle biopsy (as only the myophosphorylase isozyme is affected).
For example, in Niemann–Pick diseases A and B, sphingomyelinase is deficient in the brain and spinal cord, but also in the GIT, liver, spleen, and BM. Abnormal lipid metabolism can therefore be demonstrated in relatively easily accessible tissue such as fibroblasts.
Not only may the absence or lower activity of an enzyme reduce the amount of product of the reaction it catalyses, but it may also lead to the accumulation of precursors in the metabolic pathway:
•For example, in acute intermittent porphyria, there is ↑ urinary excretion of ↓ heme aminolevulinic acid and porphobilinogen (intermediates in the haem synthetic pathway) during an acute attack.
•↓ levels of porphobilinogen deaminase may be demonstrated in erythrocytes, leucocytes, and cultured fibroblasts.
1.Rest the patient supine for 30min.
2.Draw a baseline lactate sample from a catheter in an antecubital vein.
3.Inflate the sphygmomanometer cuff on that arm to above arterial pressure.
4.Subject squeezes a rubber ball in that hand until exhaustion.
Normally the venous lactate will rise by 2-, 3-, or even 4-fold; if it fails to rise by 1.5-fold, then there is likely to be a glycogenolysis or glycolysis defect (or the patient has not exercised sufficiently!).7
The list of diseases for which we have specific genetic tests grows each month. Rather than give a necessarily incomplete compendium, we discuss some general principles.
Several important neurological conditions may today be diagnosed by (relatively) simple genetic tests, whereas in the past biopsy was necessary. For example, Duchenne, Becker, and oculopharyngeal muscular dystrophies are associated with well-defined genetic abnormalities. Similarly, several mitochondrial cytopathies (such as myoclonic epilepsy and ragged red fibres (MERRF) and mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS)) may now often be diagnosed by finding common mutations or deletions in mitochondrial DNA.
•Genetic counselling of an index patient and his family.
•Cytogenetic or molecular diagnosis.
•Long-term follow-up of family:
•Counselling family members as they become adult.
•Coordinating care with paediatric and adult neurologists.
•Unexplained developmental delay.
•Unexplained major CNS malformation.
•The coexistence of two genetic diseases in a patient.
•FISH for suspected submicroscopic chromosomal aberrations, e.g. a p13.3 deletion may cause lissencephaly.
•Confirming a clinical diagnosis.
•Identify carriers in the family.
An ever ↑ range of diseases may be tested for. Some of these tests may be routinely available at your local clinical genetics laboratory, others at regional, national, or even supranational centres. Other tests may be available on a ‘research’ basis. It is clear, however, that tests for genetic ‘lesions’ or risk factors will become increasingly available. Rather than give an, at best, partial list of readily available tests, we give a few examples below of the kinds of tests that are available. The astute reader will spot that different mutations within a given gene can give rise to different clinical phenotypes. Indeed, recent work has shown that the same mutation in some genes can give rise to >1 phenotype—we clearly have a great deal yet to learn about the genetics of neurological diseases!
•For example, in mitochondrial (mt)DNA in MELAS and MERRF.
•For example, of dystrophin gene in Duchenne and Becker muscular dystrophies.
•For example, PMP22 gene duplication in some cases of Charcot–Marie–Tooth disease type 1 (or hereditary motor sensory neuropathy type 1 (HMSN1); deletions within this gene cause hereditary neuropathy with liability to pressure palsies (HNPP).
•Found in >10 neurological diseases (see Table 9.9).
•So far, there is no overlap in the number of repeats in controls and affected patients (except rarely in Huntington’s, in the region of 33–36 repeats).
•Anticipation (more severe phenotype and earlier onset) often reflects in ↑ number of repeats in the most recent generations (especially myotonic dystrophy).
Table 9.9 Some trinucleotide repeat diseases
| Disease | Gene | Triplet repeats | Transmission |
| Fragile X | FMR1 | CGG | X-linked |
| Myotonic dystrophy | DM | CTG | AD |
| Friedreich’s ataxia | FRDA | GAA | AR |
| Spinobulbar muscular atrophy | Androgen receptor | CAG | X-linked |
| Huntington’s disease | IT15 | CAG | AD |
| Spinocerebellar atrophy | |||
| SCA 1 | CAG | AD | |
| SCA 2 | CAG | AD | |
| SCA 3 | CAG | AD | |
| SCA 6 | CAG | AD | |
| SCA 7 | CAG | AD | |
| Dentarubropallidoluysian atrophy | DRPLA | CAG | AD |
AD, autosomal dominant; AR, autosomal recessive.
Note: SCA 6 is a CAG triplet expansion in the CACNL1A4 calcium channel gene. Other (non-triplet repeat) mutations in the gene cause other conditions—episodic ataxia type 2 and familial hemiplegic migraine.
This involves fragmenting the DNA of the gene into manageable pieces, then amplifying these so that there are multiple copies. Subsequently, various methods may be used to detect fragments with abnormal sequences, even if only differing at a single base from the ‘wild-type’. There are several such techniques, constantly being refined, and many are restricted to research laboratories.
•However, molecular genetics is proceeding at a tremendous pace, both in terms of the number of conditions with identified genetic lesions and the laboratory techniques for analysis.
•High-speed DNA sequencing will facilitate sequencing large pieces of DNA.
•For example, point mutations in the MPZ gene, which encodes P0, a component of the myelin sheath, have been found in some families with Charcot–Marie–Tooth disease type 1B.
Another area of clinical genetics which is likely to become more important is the detection of genetic ‘risk factors’ for diseases. Certain allelic variants, whilst not ‘causing’ a disease in the traditional sense, may predispose an individual to exhibiting a certain clinical phenotype or alter the age at which it might become apparent.
For example, there are three allelic variants in the apolipoprotein E (APOE4) gene e2, e3, and e4. Homozygosity for e4 is likely to be a risk factor for developing Alzheimer’s disease and for developing it at an earlier age. However, the majority of e4 homozygotes do not develop the condition (therefore, it is not ‘causative’).
Immunocytochemistry and immunoblotting (western blots) on tissue samples from the patient allow direct visualization of the presence of abnormal protein or the absence or reduced levels of normal protein, in a variety of conditions. (These techniques are not genetic in the strictest sense but are often useful in ‘genetic’ conditions.)
For example, Duchenne and Becker muscular dystrophies have absent or reduced levels of dystrophin in muscle biopsy samples.
With developments in technology and informatics, it is becoming increasingly feasible (in terms of both cost and time) to sequence the entire genome of individuals. Whole genome sequencing has resulted in the detection of rare pathogenic mutations and the determination of genetic risk factors
The 100,000 Genomes Project was established in 2012 and aims to sequence 100,000 whole genomes from NHS (England) patients with rare diseases, their families, and patients with cancer ( http://www.genomicsengland.co.uk/the-100000-genomes-project/).
Online Mendelian Inheritance in Man (OMIM) is a continually updated catalogue of ‘genetic’ diseases in man, giving data about the genotype, mode of inheritance, and clinical phenotype of thousands of disorders (not just neurological).
Manolio TA. Genome-wide association studies and the risk of disease. N Engl J Med 2010; 363: 166–76.
Online Mendelian Inheritance in Man. https://www.omim.org/.
Young AB. Huntington’s disease and other trinucleotide repeat disorders. In: JB Martin (ed.). Scientific American Molecular Neurology. New York: Scientific American, 1998; pp. 35–54.
•Measures the threshold for air (AC) and bone conduction (BC) at frequencies from 250 to 8000Hz.
•Conduction deafness: BC > AC at all frequencies.
•Sensorineural deafness: AC = BC at all frequencies, but ↑ deafness as the frequency rises.
1.Inspect the eardrum; if intact, proceed.
2.Place the patient supine with the neck flexed 30° (on pillow).
3.Irrigate the external auditory meatus with 30°C water (ice water if testing for brain death).
4.Observe for (or record*) nystagmus.
Note: (*) there are various techniques for recording eye movements that are available in specialized clinical and research laboratories.
1.Cold water induces convection of fluid in the ipsilateral lateral semicircular canal (LSCC).
2.There is less output from the ipsilateral LSCC.
3.Imbalance of signals from the two LSCCs results in eye drift towards the irrigated ear.
4.Fast-phase contraversive movements correct for eye drift (hence, nystamus with the fast phase away from the irrigated ear).
1.Prolonged nystagmus in one direction.
2.Suggests a central lesion on the side of preponderance or contralateral peripheral lesion.
Combination of clinical examination, audiometry, and caloric testing of the vestibulo-ocular reflex will help localize a lesion (peripheral vs central; left vs right).
Sensory evoked potentials or responses, Brainstem auditory evoked potentials (BAEPs, BAERs, BSAEPs), pp. 624–626.
Brandt T, Dieterich M, Strupp M.Vertigo and Dizziness, 2nd edn. London: Springer, 2014.
1 National Institute for Health and Care Excellence (2014). Head injury: assessment and early management. Clinical guideline CG176. https://www.nice.org.uk/guidance/cg176.
2 Yates D, Aktar R, Hill J; Guideline Development Group. Assessment, investigation, and early management of head injury: summary of NICE guidance. BMJ 2007; 335: 719–20.
3 Karamessini MT, Kagadis GC, Petsas T, et al. CT angiography with three-dimensional techniques for the early diagnosis of intracranial aneurysms. Comparison with intra-arterial DSA and the surgical findings. Eur J Radiol 2004; 49: 212–23.
4 Smith R, Hourihan MD. Investigating suspected cerebral venous thrombosis. BMJ 2007; 334: 794–5.
5 Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: revisions to the ‘McDonald criteria’. Ann Neurol 2005; 58: 840–6.
6 Devlin JT, Watkins KE. Stimulating language: insights from TMS. Brain 2007; 130: 610–22.
7 Gray RG, Preece MA, Green SH, Whitehouse W, Winer J, Green A. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiat 2000; 69: 5–12.
