to proceed to biopsy. It may be of use in trying to distinguish between segmental demyelination and axonal degeneration, and also in the diagnosis of a number of specific disorders such as amyloidosis, vasculitis, and sarcoidosis. The decision to biopsy must take into account the likelihood of the biopsy leading to a change in treatment, and this must be balanced against the morbidity which can be associated with this test.

Traditionally, the sural nerve was biopsied. This leads to permanent numbness affecting the lateral border of the foot. Sometimes, this can result in persistent unpleasant dysaesthesia, which can be worse than the initial symptoms. Biopsies nowadays tend to be fascicular, which at least spares a portion of the nerve, with less attendant morbidity. Normally, the specimen is analysed using light and electron microscopy, often with immunohistochemistry.

Muscle biopsy

This should only be considered after a full neurological examination, supplemented by appropriate blood tests, and often EMG. A muscle appropriate to the patient’s symptoms must be chosen, and biopsy should only take place in centres where the specimen can be processed and analysed fully, i.e. histochemistry, electron microscopy, and special studies such as immunohistochemistry.

The issue of whether open or needle biopsy is better is still controversial. Open biopsies provide a larger specimen, which can be fixed at its physiological length. Needle biopsy, however, results in less scarring, and the ability to sample multiple sites. The specimen is, however, smaller and it is more difficult to orientate.

Specific laboratory tests

Antibodies

In myasthenia, the presence of acetylcholine receptor antibodies is diagnostic, although antibody-negative myasthenia may occur, especially in more restricted forms such as ocular or bulbar myasthenia. Voltage gated calcium channel antibodies are detected in 90% of patients with Eaton–Lambert syndrome, which can superficially mimic myasthenia. In certain of the hereditary motor and sensory neuropathies (HMSN some types termed Charcot– Marie–Tooth disease), it has been possible to identify the genetic mutations. Of those HMSN with a known genetic basis, HMSN types 1 and 3 have been associated with mutations in one of several genes expressed in

Schwann cells, which produce myelin for the peripheral nervous system.

Mitochondrial diseases are a diverse group of conditions resulting from impairment of mitochondrial function, and leading to a wide range of clinical disorders. Some patients have symptoms that fulfil clearly delineated syndromes, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or myoclonic epilepsy and ragged red fibres syndrome (MERRF), but most do not. Molecular genetic studies of deoxyribonucleic acid (DNA) from blood may be analysed for mitochondrial DNA mutations. Nearly all point mutations may be detected from blood, but major structural mutations, such as deletions, require skeletal muscle for analysis.

Ischaemic lactate test

This is a physiological test of muscle function. The patient is asked to grip repeatedly, with a cuff occluding the circulation. Blood is drawn at regular intervals in order to assess lactate levels. Normally, when exercise is relatively anaerobic, then anaerobic metabolism should produce lactate. In patients with deficits in the glycolytic pathway, there is no rise in lactate levels with ischaemic exercise. In contrast, in mitochondrial disease, there can be excess lactate production.

INVESTIGATING SPECIFIC SITES

Certain constellations of clinical features are of great localization value. The tempo of onset of symptoms is then of use in determining the type of pathological process responsible for these anatomically localizable syndromes.

CRANIO-CERVICAL JUNCTION

Lesions at the cranio-cervical junction may result in symptoms of poor balance (60). There may be a history of loss of function on one side followed by progression to signs to all four extremities. Neurological examination may reveal ataxia and cerebellar signs, together with brisk reflexes and upgoing plantars. Down-beating nystagmus, if present, points to the cranio-cervical junction. Although CT may be sufficient, the cranio-cervical junction is best imaged with MRI (61).

CEREBELLO-PONTINE ANGLE

A common cause of lesions at the cerebello-pontine angle is acoustic neuroma or other tumours such as meningioma (62, 63). Patients with lesions here tend

61 Magnetic resonance image showing Chiari malformation resulting in secondary hydrocephalus.

62 Diagram of a cerebello-pontine angle tumour, compressing adjacent structures.

to present with mild vertigo or ataxia, and there may be accompanying ipsilateral occipital pain. Examination often reveals asymmetrical sensorineural hearing loss on examination. In the event of delayed diagnosis, as the tumour progresses there may be facial pain, numbness, and paraesthesia due to involvement of the trigeminal nerve. Depressed corneal reflex will be evident. Should the tumour result in hydrocephalus, the symptoms and signs of raised intracranial pressure will appear.

PITUITARY/CAVERNOUS SINUS

Lesions of the pituitary fossa may present with local space-occupying effects, or with endocrine symptoms depending on whether an active hormone is being released. Local mass effect can result in nonspecific headache. On examination, the finding of a visual field defect should raise suspicion of a pituitary lesion. Pressure on the inferior aspect of the optic chiasm results in a superior temporal quadrantanopia, but tumour progression will lead to bitemporal hemianopia. In some instances, lateral expansion will lead to compression of nerves lying in the walls of the cavernous sinus, especially the third nerve (64, 65).

Endocrine effects depend on whether there is hypersecretion or hyposecretion of hormones, and on which hormone is being affected. Should there be hypersecretion of growth hormone (GH), then this will result in acromegaly. This presents clinically with enlargement of face, hands, and feet, with coarsening of the skin. A tumour producing increased prolactin will result clinically in women with infertility, amenorrhoea, and galactorrhoea. In men, impotence may occur. An adrenocorticotrophic hormone- (ACTH) producing pituitary tumour will result in the features of Cushing’s syndrome. This includes facial

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VI nerve

Sphenoid sinus

mooning, hirsutism, central obesity, and muscle weakness.

Investigation of lesions affecting the pituitary or cavernous sinus primarily involves neuroimaging and tests of endocrine function. The imaging modality of choice for investigating pituitary lesions is MRI (66). This gives excellent anatomical detail, and can show whether there is suprasellar extension and whether adjacent structures such as the walls of the cavernous sinus are involved. Given the close proximity of the pituitary to the optic chiasm, it is important to test visual fields as a means of monitoring involvement of visual pathways. This is best done at the bedside by assessing peripheral visual fields using a red hatpin. It may be supplemented by more detailed Goldmann perimetry, available in ophthalmology clinics.

Hypersecretion may be diagnosed by measuring blood levels of the relevant hormone. While many endocrine presentations of pituitary tumours are due to hypersecretion, it is also possible for pituitary lesions to present clinically with signs of impairment of pituitary secretion. This may present clinically as adult GH deficiency syndrome (weight gain, loss of libido, fatigue), muscle weakness and fatigue, or with the symptoms of hypothyroidism. Low levels of pituitary hormone in the presence of low target gland hormones confirm hyposecretion. This can be further

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investigated by combined pituitary function stimulation tests comprising the insulin tolerance test, also with gonadotrophin releasing hormone (GnRH) and thyrotrophin releasing hormone (TRH) injection.

DISEASE AT ‘SHARED’ SITES

Orbit

Orbital disorders may present to the neurologist as well as to the ophthalmologist, and it important that neurologists are aware of the appropriate investigations for this area.

Methods of visual field testing

It must be remembered that confrontation using a red pin is a relatively crude means of mapping visual fields, both for peripheral vision and for assessing the blind spot. Peripheral visual fields are better tested with a Goldmann perimeter (67). Here, a moving target is brought in from the periphery, and the patient must indicate as soon as he is aware of the target. It is thus possible to map out peripheral visual fields well.

While central fields may be assessed using a Goldmann perimeter, this is more accurately done using the Humphrey field analyser, which records the threshold at which a static light source is seen at various central points.

66 Magnetic resonance image of a pituitary tumour (arrow).

68

68 Magnetic resonance image showing a small tumour superior to the left eye.

Imaging

Tumours of the orbit, or inflammatory conditions, are best visualised using MRI (68) rather than CT (69).

Neurophysiology

Visual evoked responses (VERs) have been described above, but are a useful means of assessing the integrity of the visual pathway from retina to occipital cortex.

Electroretinography (ERG) is a means of assessing rod and cone photoreceptor function, and is of use in assessing retinal degeneration and dystrophy.

Fluorescein angiography

This involves intravenous injection of aqueous fluorescein. A photograph of the fundus is taken before and after injection. This technique demonstrates choroidal and retinal vasculature, and can detect vascular occlusion and retinal haemorrhages. True optic disc swelling results in leakage of fluorescein, while pseudopapilloedematous discs do not leak.

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69 Computed tomography scan showing a left optic nerve meningioma. (Note Left is left on this scan.)

The ear

Many conditions such as dizziness may present equally to a neurologist as to an ear nose and throat surgeon. One should therefore be familiar with the relevant investigations.

Auditory system

Weber’s and Rinne’s tests done as part of the neurological examination will usually allow classification of hearing impairment as being sensorineural or conductive, and will localize which is the impaired ear. These tests are, however, supplemented with further investigations including audiometry. Pure tone audiometry involves air conduction by means of a pure tone administered through headphones, with masking noise applied to the contralateral ear (70). Bone conduction is assessed by means of an electromechanical vibrator. Airconducted sound requires a functioning ossicular system as well as cochlea and VIII nerve, while bone conduction bypasses the ossicles.

Speech audiometry uses pretaped words rather than tones, but involves the same principles as the above.

Stapedial reflex decay

Normally, a loud stimulus causes reflex contraction of stapedius, with subsequent reduced compliance of the tympanic membrane. In this test, an activating tone is applied to the ear under test, and the tympanic membrane impedance is monitored in the contralateral ear. Rapid decay of the reflex response suggests an auditory nerve lesion.

Auditory brainstem evoked potential

This has been covered earlier in the chapter.

Vestibular system

Caloric testing

The vestibular system may be tested clinically using the Hallpike manoeuvre. Further investigation of the vestibular system relies on caloric testing, which utilizes the vestibulo-ocular reflex. In this test, water at 30°C (86°F) is irrigated into the ear. Nystagmus usually occurs after 20 seconds, and lasts for more than 1 minute. The test is then repeated 5 minutes later with water at 44°C (112°F). Cold water reduces vestibular output from one side, causing an imbalance and producing eye drift towards the irrigated ear, with rapid corrective movements to the opposite ear. Hot water reverses this, increases vestibular output and changes the direction of nystagmus. Time until cessation of nystagmus is plotted for each ear, at each temperature (71).

Reduced duration of nystagmus is termed canal paresis. This may be due to a peripheral or central lesion. A more prolonged duration of nystagmus in one direction than the other is called directional preponderance. It can be due to a central lesion ipsilateral to the preponderance, or from a contralateral peripheral lesion.

Combined with audiometry, these tests should differentiate peripheral from central lesions.

Electronystagmography

Although nystagmus may be observed clinically, it is

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Damage to the labyrinth, vestibular nerve or nucleus results in one of two abnormal patterns, or a combination of both.

R

71 Caloric testing illustrating normal response, canal paresis, and directional preponderance.

possible to assess nystagmus in a more quantitative manner by means of electronystagmography (ENG). These studies of eye movements are performed in darkness, in order to eliminate the stabilizing effects of visual fixation.