Neurology: The principle of neurology and psychiatry

Approach to the patient with neurological problems

The overall aim of the history, examination and investigation of a patient is to establish if there is a neurological problem and if so:

• WHERE is the site of that pathology?
• WHAT is the nature of the abnormality?
• HOW can one best investigate it?
• HOW can one best treat it?

History taking

This may require input from a carer/spouse/relative/friend in the case of disorders of altered consciousness (e.g. epilepsy) or central nervous system (CNS) degenerative processes or major injury (e.g. head injury; Alzheimer’s disease), especially if there is frontal lobe damage as this causes patients to lose insight into their problems.

The main elements of the history require the following information:

• What is the primary complaint?
• When did it begin?
• How has it progressed?
• Is it a recurrent problem?
• What associated features are seen with the main complaint?
• Have you had any neurological problems/injuries in the past?
• Is there a family history of neurological problems?
• What medication are you taking?
• What medical illnesses to date do you have or have had?
• What is your occupation?
• Do you smoke/drink/use illicit drugs?
• Any recent travel abroad?

Obviously, further direct questioning can be targeted to try to better define the nature of the problem depending on the initial complaint. It is worth bearing in mind that psychiatric problems can present with neurological symptoms.

Examination

What the patient complains about is a symptom and what you find on examination is a sign. The process by which one examines the nervous system is detailed. However on occasions it may be necessary to also do a brief psychiatric assessment, and in cases where the disorder is thought to not be neurological then examination of other systems is mandatory (e.g. cardiovascular system with blackouts).

Investigations

The number and type of investigations is driven by the answers to the above questions 1–3. Many tests are non-invasive and easy to do, but careful consideration must always be given as to why a test is being done and whether it is necessary.

Blackouts

This can be due to epilepsy, disturbances of circulation (faints, cardiac dysrhythmias, aortic stenosis) or on occasions due to anxiety/psychiatric problems. It is important to get a clear history of when the attacks occur, what causes them and what happens during them, which typically requires a witnessed account.

Dizziness

This is a very common problem and it is often hard to make a diagnosis. It is rarely due to CNS disease. It is more commonly a feature of an inner ear problem or anxiety with hyperventilation.

Sensory symptoms

Many patients complain of focal sensory disturbances – numbness or tingling. If very focal and not associated with weakness then the chances of finding a cause for it are very rare. Indeed if no ‘hard’ signs can be elicited, again, it is unlikely that a cause will be found.

Fatigue

This is a very non-specific symptom and rarely yields to a diagnosis. It is important to differentiate between fatigue/tiredness and:

• weakness = motor neurone involvement;
• daytime somnolence = sleep problem;
• fatiguable weakness = neuromuscular junction problem.

Fatigue is a common feature of depression but can also be seen in multiple sclerosis (MS) and Parkinson’s disease.

Did you know?

The first neurology book in English was written in 1650 by Robert Pemell, an English country physician. It was entitled De Morbis Capitis or Of the Chief Internal Diseases of the Head.

Examination of the nervous system

The examination of the nervous system can be broken down into a number of separate assessments.

Cognitive examination

There are a number of widely available assessment tools including the Mini Mental State Examination (MMSE; <25 is taken to indicate dementia) and the revised Addenbrooke’s Cognitive Examination (ACE-r). However in clinic, targeted tests of cognition are very helpful at delineating the main site of pathology causing cognitive problems. However, these tests are only useful to do if the patient has a normal level of consciousness, is able to pay attention and has no major problem with language.

General

• Orientation in time, person and place: if these cannot be correctly answered (assuming the patient has no major language deficits) then the patient is either acutely confused or severely demented, in which case the remainder of the cognitive examination is unlikely to be helpful.

Frontal lobe function

• Verbal fluency: number of words generated beginning with a certain letter (e.g. ‘s’) or specific category (e.g. animals) over a 60- or 90-second period.
• Concentration: the ability to take in and repeat back immediately a list of objects or a name and address.
• Primitive reflexes: including pouting of the lips when they are tapped and grasping the examiner’s hand when it is gently moved across the patient’s hand.
  

Parietal lobe function

• Attention: or neglect of visual or somatosensory stimuli in the contralateral sensory hemifield.
• Dyspraxia: the patient is unable to form, copy or mime gestures and common tasks (e.g. combing hair).
• Visuospatial function: the ability to copy drawings (e.g. interlocking pentagons).

Temporal lobe function

• Anterograde memory: the ability to remember a standard name and address given to the patient (e.g. Peter Marshall, 42 Market Street, Chelmsford, Essex) 5 minutes after it has been given. It is though important to ensure that the patient has taken in information in the first place.
• Language: language assessment involves listening to spontaneous speech for content and fluency, naming objects, repeating phrases (e.g. ‘no ifs, ands or buts’), following commands, reading and writing.

Cranial nerves

• Olfactory nerve: each nostril is tested separately with a range of standard odours.
• Optic nerve: visual acuity for each eye is tested using standard eyesight charts. The visual fields for each eye are then tested with examination of the blind spot if necessary . The fundi (back of the eye) are examined with an ophthalmoscope looking for abnormalities of the retina and optic disc, e.g. swollen (papilloedema) or pale and atrophic (optic atrophy). Colour vision (using the Ishihara colour plates) and pupillary responses can also be tested.
• Oculomotor, trochlear and abducens nerves: ptosis, pupillary abnormalities and eye movements.
• Trigeminal nerve: sensation is tested in all three divisions of the trigeminal nerve and the power of the jaw muscles. In some cases, the corneal reflex is tested by lightly touching the cornea with cotton wool.
• Facial nerve: the power of facial muscles is tested, e.g. the patient screws up their eyes tightly, blows out their cheeks or purses their lips. The examiner should not be able to overcome any of these movements.
• Vestibulocochlear nerve: hearing is tested in each ear by gently whispering a number into each. More formal testing can be performed with tuning forks.
• Glossopharyngeal and vagus nerves: the patient opens their mouth wide and says ‘ahhhhhh’ so that the movement of the palate can be assessed. The gag reflex can be tested by gently placing a spatula against the posterior pharyngeal wall and noting any reflex movement of the palate. Testing the strength and character of a cough can also be helpful in some cases.
• Spinal accessory nerve: this is tested by getting the patient to turn their head to the right and left and shrug their shoulders. The examiner should not be able to overcome this movement.
• Hypoglossal nerve: this is tested by looking at the tongue in the floor of the mouth for wasting or fasciculation; it is then protruded from the mouth and any deviation from the midline noted. Power is tested by getting the patient to push the tongue into each cheek, assuming they do not have any significant facial weakness.

Motor system examination of the limbs

The examination of the motor system includes:

• Observation: involuntary movements, wasting, weakness, fasciculation, scars or deformities.
• Tone: the limb is gently moved and its stiffness assessed. Stiffness is increased in Parkinson’s disease or upper motor neurone (UMN) lesions and decreased in lower motor neurone (LMN) or cerebellar lesions. Sometimes the tone is increased because the patient cannot relax or is in pain.
• Power: movements are assessed and scored according to the Medical Research Council (MRC) rating scale (see figure).
• Coordination: the ability to coordinate movements in the upper limb is tested by getting the patient to touch the examiner’s finger and then their own nose with the same finger after it has slowly moved about in front of the patient. This may be abnormal if there is weakness, sensory loss or cerebellar disease. In the lower limb,
  coordination is tested by getting the patient to walk normally, then heel–toe walking and finally by getting the patient to run their right/ left heel along their left/right shin, respectively, while lying down.
• Reflexes: these are tested by tapping the tendons at certain sites in the upper and lower limb. Reflexes can be absent, reduced, normal or brisk. The latter implies a UMN lesion while reduced or absent reflexes implies a dysfunction in part of the spinal monosynaptic reflex.
• Plantar responses: the sole of the foot is gently scratched along its lateral aspect and the toes should fan out and the big toe go down (flexor or normal plantar response). If the toes point up and this is not a withdrawal response, it implies a UMN lesion.

Sensory examination

Sensation in the limbs is tested at the extremities and in the dermatomes using a number of tests.

• Light touch: cotton wool is gently applied to the skin, having checked that the patient can feel it normally (test on face first, assuming there is no trigeminal sensory loss).
• Pinprick: a blunted pin is used.
• Temperature: cold and hot tubes or objects are used.
• Vibration perception threshold (VPT): a tuning fork is applied to the distal interphalangeal joint or big toe. The patient must feel it vibrating, not just feel it being applied to the joint. If it is not felt to vibrate, the fork is moved proximally.
• Joint position sense (JPS): this is tested by slightly moving the terminal joint in the hand or toe, having checked that the patient understands what is meant by up and down movements. This movement should be very slight, as JPS is very sensitive in humans. If the movement cannot be detected then larger movements are made at these joints before moving to more proximal joints, in the same way as for VPT.

Did you know?

The plantar response was originally described by Joseph Babinski in 1896, whose brother was a famous cook and engineer.

Investigation of the nervous system

The key to investigating any patient is through their history and examination, as this will highlight the likely nature and site of the problem.

History and examination

At the end of the history and examination one should have formulated a hypothesis of where the problem lies and what the problem could be, which will then guide investigations.

Blood tests

A large number of tests are available (see figure for examples).

Imaging

• Plain X-rays are rarely of value in the diagnosis of neurological disease, unless one suspects the patient has a related disease in another site such as the chest (e.g. lung cancer).

• Computed tomography (CT) gives detailed X-ray images of the brain, skull and lower spine. It is useful for diagnosing structural lesions such as tumours, major strokes or skull fractures. It is widely available but has limited resolution especially in the posterior fossa and cervicothoracic spinal cord.

• Magnetic resonance imaging (MRI) is a noisy, claustrophobic procedure which relies on patient cooperation. It provides detailed images of all parts of the brain and spinal cord and the use of different sequences has increased its utility and diagnostic strength. It does not involve any radiation.

• Magnetic resonance angiography and venography (MRA/MRV) scans delineate the major blood vessels to, within and from the brain. They are primarily used to look for significant narrowing (stenosis) of the extracranial carotid arteries in the neck, aneurysms in the brain and blockage of the major venous sinuses in the brain, but are not as sensitive as angiography.

• Angiography involves the passing of a small catheter to the origin of the major blood vessels of the brain (both carotid and vertebral arteries), and a small amount of dye is injected. The dye can then be followed using a video and images captured rapidly over time as the dye passes through the vascular tree. The procedure is invasive and carries a small risk of complication, but is useful in accurately delineating any vascular abnormalities (e.g.
  carotid stenoses, aneurysms, arteriovenous malformations and venous sinus thrombosis). It can also be used to look for specific vascular abnormalities in the spinal cord.

• Myelography is rarely used nowadays to delineate abnormalities in the spinal cord because of the non-invasiveness and resolution of MRI. However, it can be helpful in some circumstances and involves injecting a radio-opaque dye via a lumbar puncture into the subarachnoid space around the spine.

• Single photon emission computed tomography (SPECT) involves radioactive isotopes which typically provide information on perfusion within the brain. It has low resolution.

• Positron emission tomography (PET) detects the release of positrons from specific substances that bind to certain chemical sites within the brain. It is only used to localize small occult tumours in patients with suspected paraneoplastic syndromes at the moment.

Electrical tests

• Electrocardiography (ECG) is an electrical recording from the heart, and is performed in many patients with neurological disease, especially those with muscle disease, blackouts or some genetic disorders (e.g. myotonic dystrophy).

• Electroencephalography (EEG) measures the electrical activity and rhythms of the brain and is helpful in patients with decreased levels of consciousness, epilepsy and some patients with sleep disorders (e.g. narcolepsy).

• Nerve conduction studies (NCS) involve stimulating both sensory and motor nerves and measuring the response. The general principle is that one stimulates at one site of the nerve and records at another site or the muscle it innervates. The size and speed of the response are important. Loss of myelin (demyelination) slows the speed of conduction, while a loss of axons gives a smaller response but normal conduction velocity. It is useful in determining whether the patient has a neuropathy, what type (demyelinating versus axonal) and the extent (focal or generalized).

• Electromyography (EMG) involves placing a needle into the muscle and recording the electrical activity within it. It is useful in the diagnosis of muscle disease and in patients with motor neuronal loss as occurs in motor neurone disease (MND) because EMG can show the extent of denervation, helping in the diagnosis.

• Evoked potentials (EPs) can be recorded from the visual pathway (visual-evoked potential or responses; VEP), auditory pathway (brainstem auditory-evoked potential BSAEP) or peripheral nerves in the arms or legs (somatosensory-evoked potential). The test involves stimulating the peripheral receptor (eye, ear or median/posterior tibial nerve) and measuring the cortical response. This gives a measure of conduction that has both a peripheral and CNS component. The most commonly used test is VEP in multiple sclerosis to look for asymptomatic demyelination in visual pathways.

• Central motor conduction time (CMCT) measures the time from stimulating the motor cortex to measuring a muscle response in the periphery such as the hand. It is not routinely available and can be used as a measure of integrity of the descending corticospinal tract assuming that there is no dysfunction within the peripheral
  motor apparatus.

• Thermal thresholds are a subjective test designed to look at small fibre responses in patients. It relies on the patient detecting changes in temperature in the hands and feet. It is not routinely available.

Cerebrospinal fluid analysis

Cerebrospinal fluid (CSF) can be obtained from a number of sites but is routinely obtained by a lumbar puncture, which involves passing a small needle into the subarachnoid space in the lower lumbar spine. CSF should be clear and sent for analysis to include the following:

• Numbers of certain cell types are typically raised in infections (e.g. meningitis and encephalitis) as well as in malignant meningitis (where cancer cells seed themselves along the meninges).

• Culture of the CSF to look for infective organisms, including Gram staining in meningitis and polymerase chain reaction (PCR) for the causative organism in some infections of the CNS (e.g. herpes simplex virus in herpes encephalitis).

• Glucose levels, which can be low in certain types of infection or meningitis and metastatic tumours growing in the meninges.

• Protein levels, which can be raised in some types of neuropathy, tumour and in lesions blocking spinal CSF flow.

• Oligoclonal bands indicative of immunoglobulin synthesis specifically within the CNS, typically seen in multiple sclerosis.

Nerve/muscle biopsy

In cases where there is evidence of nerve or muscle disease, a biopsy may be helpful in identifying the defect more specifically. Typical biopsy sites are the radial and sural nerves and the quadriceps and deltoid muscles.

Brain biopsy

This is routinely performed in patients with brain tumours to confirm the diagnosis and to some extent predict prognosis. In some cases of progressive neurological disease for which no obvious cause can be found, a biopsy looking specifically for inflammation in the blood vessels (vasculitis) as well as prion disease may be considered.

Did you know?

The first documented experiments with EMG were undertaken by Francesco Redi in 1666.

Imaging of the central nervous system

Imaging of the central nervous system (CNS) is essentially designed to look either at structure (computed tomography [CT], magnetic resonance imaging [MRI], angiography) or function (functional MRI [fMRI], positron emission tomography [PET], and single photon emission CT [SPECT]). In clinical practice it is the former that is the mainstay of practice, with the latter tests reserved for patients being investigated for specific problems or as part of a
research project.

• In general structural scanning is undertaken to determine if there is any abnormality in the CNS on imaging.

• If there is an abnormality, then where is it and does it fit with the history and clinical examination?

• What is the likely nature of that abnormality pathologically based on its radiological appearance?

This information can be used for the future investigation and management of patients with neurological disorders. This chapter outlines the major imaging modalities used in clinical practice, their indications, value and drawbacks.

Structural imaging

CT imaging

• Basic principle: this technique uses X-rays to scan the brain or spine (typically lumbar) and then reconstruct an image of that structure; it can be performed with or without a contrast agent, the latter being used to better define blood vessels and abnormalities in the blood–brain barrier.

• Use: imaging of the brain looking for major abnormalities, in particular stroke, head trauma, hydrocephalus or tumour, especially in the acute medical situation. It can also be used to look for skull fractures and prolapsed intervertebral discs in the lumbar spine, and in some cases to look for cerebral aneurysms.

• Advantages: widely available, and often gives useful and vital information especially in acute situations. It is well tolerated by nearly all patients, even those who cannot fully cooperate, and if general anaesthesia is needed, this is more easily performed with CT than MRI.

• Disadvantage: it has poor contrast resolution compared with MRI and as such is not so good at identifying lesions in the posterior fossa and cervicothoracic spine. This is because dental fillings can often result in several artefacts on scans of the posterior fossa. It also involves radiation, which can be an issue in some situations – e.g. pregnancy.

MRI

• Basic principle: this technique places the patient in a strong magnetic field which is then subject to a series of magnetic perturbations (scan sequence), which alter the orientation of hydrogen ions, such that their change and subsequent shift back to normal position is detected. Thus, it does not use X-rays and is very sensitive to subtle changes in water content, which makes it a highly sensitive scan.

• Use: most patients with neurological problems should have an MRI scan, given its superior spatial resolution compared with CT scanning and the fact that any part of the neural axis can be scanned with it. Thus, it is employed in patients with chronic neurological problems (e.g. multiple sclerosis) as well as those with evolving acute disorders (e.g. herpes encephalitis). It can also be used with a contrast agent (gadolinium) and to image blood vessels both on the arterial side (magnetic resonance angiography [MRA]) looking for carotid artery disease or intracerebral aneurysms and on the venous side (magnetic resonance venography [MRV]), especially to look for major venous sinus thromboses.

• Advantages: high spatial resolution and the fact that any part of the neural axis can be imaged, along with the major vessels, without recourse to X-ray exposure or invasive procedures.

• Disadvantage: it is a noisy, claustrophobic experience and requires the patient to be cooperative to some extent. Some patients cannot cope with the claustrophobia while agitated patients will move in the scanner causing major artefacts on the images. It also cannot be used in patients with metallic magnetic materials such as a cardiac pacemaker.

Angiography

• Basic principle: this is the imaging of blood vessels and it can be carried out using CT and MRI, but in some cases it requires the direct visualization of blood vessels using a radiolucent contrast agent injected into an artery with video fluoroscopy to follow its course. Thus, the flow of the dye can be followed through the vasculature and X-rays taken to capture various different phases of the injection; this can identify problems on the arterial and venous sides of the circulation.

• Use: its main value is the identification of vascular abnormalities such as aneurysms, arteriovenous malformations and venous sinus disease. In all cases angiography is either performed to confirm an equivocal MRA/MRV result or as a prelude to a more invasive procedure to deal with the underlying abnormality such as the obliteration of vascular malformations through intravascular occlusion techniques (gluing or coiling).

• Advantage: it is the most high-resolution scan for identifying vascular abnormalities and is essential if intravascular interventional therapies are being considered.

• Disadvantage: it is an invasive procedure with a small but nevertheless real complication rate of stroke and local haemorrhage/ haematoma at the site at which the catheter is passed into the artery (typically the femoral artery in the groin).

Functional scanning

This embraces SPECT, PET and fMRI. Although there are a number of different types of scan, they can be thought of as
looking at either:

• Blood flow/metabolism, using glucose and oxygen markers to reflect neuronal activity and pathology, such that a loss of activity reflects an area that contains dysfunctional or dead neurones. So, for example, in Alzheimer’s disease, there will be hypoperfusion in the parietotemporal cortices. Such ‘metabolic’ scans can be undertaken
  for diagnostic and therapeutic purposes in some patients in routine clinical practice. Another related approach, which is currently only used in research, relies on looking at oxygen extraction in areas of the brain while the patient is being tested on a particular task while being imaged in the MRI scanner. The resultant scan will show which areas of the brain are activated by that task. This is called fMRI, and has been used, for example, to see which brain areas are activated by specific types of cognitive or visual processing tasks.

• Specific neurochemical markers which are used to identify and label particular aspects of a neurotransmitter pathway. In Parkinson’s disease this may involve looking at the dopamine transporter (e.g. DAT scans) or certain types of dopamine receptors (e.g. 11C-raclopride labelling of D2 receptors in PET). The former types of scan are found in many nuclear medicine departments and are widely available, while PET scanning is still only an experimental tool and found in a few research centres. However, [18F]2-fluoro- 2-deoxy-D-glucose (FDG)-PET scanning is being increasingly used to find small tumours in patients with suspected paraneoplastic syndromes. This is because they can detect small metabolically active tumours that cannot be seen using traditional imaging modalities.

Did you know?

The first PET scanner was built in 1961 and was nicknamed the head shrinker.

Clinical disorders of the sensory systems

Disturbances in the sensory pathways can produce one of two main symptoms:

• negative ones, with a loss of sensation such as numbness or analgesia;
• positive ones, such as pins and needles (paraesthesiae) or pain.
  These symptoms can arise from many different sites along the sensory pathways, but it is often the distribution of sensory change that points towards the likely site of pathology.
  In order to determine the nature and cause of the sensory disturbance a full history and examination is needed along with appropriate tests. Most patients with isolated sensory symptoms do not yield to a diagnosis but the most common causes are neuropathies and multiple sclerosis.
  A typical screen of tests for patients with sensory symptoms involves blood tests, nerve conduction studies (NCS) and magnetic resonance imaging (MRI) of brain and spinal cord. In all cases it is important to remember that non-neurological causes, e.g. hyperventilation.

Peripheral nerves

Diseases of the peripheral nerves can cause sensory disturbance. This can either be caused by focal nerve entrapment or a generalized neuropathy, in which case the disease process can target either the large or small fibres or both. Common focal nerve entrapments include:

• The median nerve at the wrist (carpel tunnel syndrome). Patients typically present with aching in the forearm especially at night, weakness of some of the thumb muscles and loss of sensation over the thumb and adjacent two and a half fingers. It can resolve spontaneously but in cases where it does not, simple splinting, steroid injection or even surgical decompression is often curative.
• The ulnar nerve at the elbow. Patients present with wasting of most of the intrinsic hand muscles with weakness and loss of sensation in the hand involving the little and half of the ring finger but without involvement of the forearm. It can be treated by surgical transposition of the nerve in some cases.
• The common peroneal (or lateral popliteal nerve) can be trapped around the knee. Patients typically present with foot drop and numbness on the outer aspect of the foot.
  Generalized neuropathies may be caused by many disorders and if large fibres are preferentially involved then there is a loss of joint position sense, vibration perception and light touch along with absent or reduced reflexes. These neuropathies are rarely purely sensory and often associated with weakness and wasting. The typical pattern of sensory loss in these neuropathies is ‘glove and stocking’ which, as the name implies, reflects the symmetrical loss of sensation in all four limbs to the wrist/forearm and to the ankle/shin.
  In some cases patients complain of much pain but paradoxically have reduced sensation for pain and temperature. These patients are more likely to have small fibre neuropathy. Rarely, the dorsal root ganglion cell (as opposed to the peripheral nerve) is targeted by the disease process. In these instances there is a devastating loss of proprioception which greatly compromises motor function.
  Peripheral pain syndromes : it is always important to remember that pain is more often the result of non-neurological causes such as arthritis or local tissue damage.
  The nerves as they emerge out of the spinal column can be trapped typically by bony spurs or intervertebral discs and give sensory disturbance along that nerve root. Patients normally complain of pain radiating down that nerve root with sensory abnormalities confined to that dermatome. This commonly happens in the cervical and lumbar region and may require surgical decompression especially in cases where there is weakness, wasting and loss of the appropriate reflexes.

Spinal cord

Syringomyelia

Syringomyelia is the development, for a number of reasons, of a cyst or cavity around or near to the central canal, usually in the cervical region, which tends to spread over time up and down the spinal cord. The lesion typically disrupts the spinothalamic tract (STT) fibres as they cross just ventral to the central canal, resulting in a dissociated sensory loss, i.e. reduced temperature and pain sensation at the level of the lesion but normal light touch, vibration perception and joint position sense. In addition, there may be motor involvement because of expansion of the cyst into the ventral horn or dorsolaterally into the descending motor tracts and other ascending sensory pathways.

Subacute combined degeneration of the spinal cord

This is usually associated with pernicious anaemia and a lack of vitamin B12. It is characterized by demyelination and eventually degeneration of the dorsal columns (DCs), the spinocerebellar (SCT) and corticospinal tracts (CoST) as well as damage to peripheral nerves (peripheral neuropathy). Patients therefore develop a combination of paraesthesiae and sensory loss (especially light touch, vibration perception and joint position sense) with weakness and incoordination. The weakness may be of both an upper and lower motor neurone type.

Brown–Séquard syndrome

This describes a lesion involving half of the cord such that there is an ipsilateral loss of position and tactile senses (DC sensory information), a contralateral loss of temperature sensation originating from several segments below the lesion (STT sensory information), and ipsilateral spasticity and weakness because of involvement of the CoST pathway.

Anterior spinal artery syndrome

This syndrome describes the situation when there is occlusion of the artery providing blood to the anterior two-thirds of the cord.
The patient has weakness and sensory loss to temperature and pain with preservation of DC sensory modalities such as joint position sense and vibration perception.

Transverse myelitis

Transverse myelitis (not shown in figure) describes a complete lesion of the whole spinal cord at one level that produces a complete sensory loss with weakness from that level down. The weakness is characteristically caused by a disruption of both the descending motor pathways and the spinal motor neurones. It is typically seen as a part of multiple sclerosis or a secondary acute demyelinating process in response to infection such as an atypical pneumonia.

Brain

Abnormalities in supraspinal sites can result from a variety of causes and depending on the disease process and site determines the type of sensory disturbance. Typically, hemispheric lesions give a loss of sensation down the contralateral side of the body. Brainstem lesions give rise to a range of sensory deficits depending on the exact level of the lesion. For example, a pontine lesion can give ipsilateral sensory loss of the face but contralateral sensory loss in the limbs.
Cortical lesions can give a loss of sensation if the primary somatosensory cortex is involved, or can give more complex sensory deficits such as astereognosis (an inability to recognize objects by touch) or even sensory neglect or inattention. These latter abnormalities are typically seen with lesions of the posterior parietal cortex.
In some cases, irritative lesions of the primary sensory cortex give rise to simple partial seizures in which the
patient experiences brief migrating sensory symptoms up one side of the body. This can also be seen in some patients with transient ischaemic attacks (TIAs).
Pain syndromes can also develop with central lesions and this is best seen in small thalamic vascular events, where dysaesthesia is found in the contralateral limb in a typically diffuse distribution.

Did you know?

The word paraesthesia derives from the Greek words para (meaning beside or abnormal) and aisthe¯sis (meaning sensation) and was first used in 1860.

Clinical disorders of the motor system

Disturbances in the motor pathways can produce a range of disorders of movement. These typically involve:

• the basal ganglia, causing abnormal involuntary movement without any effect on power, reflexes or coordination.
• the cerebellum and its connections, causing problems with coordination without any changes in power or reflexes;
• the motor neurones (lower or upper), causing weakness and changes in muscle tone and reflexes;
• the neuromuscular junction (NMJ), causing fatiguable weakness;
• the muscle, causing weakness;
  In order to determine the nature and cause of the motor disturbance a full history and examination should be undertaken along with appropriate tests. The majority of patients with isolated motor symptoms have either Parkinson’s or motor neurone disease, although by far the most common clinical scenario is the patient with both motor and sensory abnormalities as a result of strokes or damaged nerves as they emerge or pass along the limb.
  A typical screen of tests for patients with motor symptoms involves blood tests, nerve conduction studies (NCS), electromyography (EMG) and magnetic resonance imaging (MRI) of brain and spinal cord.

Muscle

The typical features of a muscle disease are weakness, which may relate to exercise, and, on occasions, muscle pain (myalgia). The age and rate of progression is often helpful in determining the type of muscle disease, e.g. progressive slow weakness without pain from childhood would suggest a degenerative muscular dystrophy, while a short history of painful weakness in adulthood would suggest an inflammatory myositis. The distribution of weakness is also helpful in defining the likely type of muscle disease, e.g. proximal arm and leg weakness in limb girdle muscular dystrophy. The investigations that are especially useful in muscle disease are blood tests to look at levels of
muscle-specific creatine phosphokinase (CPK) – a measure of muscle damage; EMG and muscle biopsy. In some cases genetic testing is of value, especially if the muscle weakness is associated with myotonia and other features of myotonic dystrophy.

Neuromuscular junction

Patients with these disorders present with a history of weakness that gets worse with continued use of the muscle. The most common disorder of the NMJ is myasthenia gravis, which typically presents in early or late adulthood with fatiguable diplopia, ptosis, facial and bulbar weakness and proximal limb weakness. The examination confirms weakness that may be present at rest but clearly gets worse with exercise. Patients can present as a neurological
emergency if there is bulbar and respiratory failure. Diagnosis typically relies on history and examination, the presence of acetylcholine receptor (AChR) or muscle-specific kinase (MUSK) antibodies, a positive response to a short-acting acetylcholinesterase inhibitor (Tensilon test) and abnormalities on repetitive stimulation with NCS and EMG. Muscle biopsy is not necessary.
In some patients myasthenia gravis is associated with either enlargement (hyperplasia) or a tumour of the thymus gland. Other myasthenic syndromes are rare.

Peripheral nerves

Damage to the peripheral nerves will generally give both sensory and motor symptoms and signs. However, the peripheral motor nerve can be preferentially involved in some neuropathies as well as in conditions such as poliomyelitis and motor neurone disease, which target the actual motor neurone cell body in the ventral horn of the spinal cord and/or brainstem. The typical features of damage to the peripheral motor nerve are weakness, wasting, fasciculation and loss of reflexes – a lower motor neurone (LMN) lesion. Investigation of LMN syndromes involves excluding nerve entrapment as it exits the spinal cord by MRI imaging, along with NCS and EMG – the latter showing features of denervation with spontaneous motor discharges from the muscle that has lost its normal innervation.

Spinal cord

The involvement of spinal cord pathways gives a variety of motor syndromes. In rare cases there is involvement of spinal cord interneurones, leading to continuous motor unit activity (CMUA) and stiff man syndrome. Involvement of descending motor pathways from the brain in the spinal cord causes an upper motor neurone (UMN) syndrome of weakness, spasticity, increased reflexes, and clonus and extensor plantars. It is unusual for this pathway to be selectively involved in spinal cord pathology and when it does happen, the patient often also has LMN signs and has a form of motor neurone disease called amyotrophic lateral sclerosis or Lou Gehrig disease. However, if only UMN signs are seen then the patient is said to have primary lateral sclerosis. Structural lesions of the spinal cord typically produce a combination of motor and sensory signs and symptoms. Investigation involves MRI, with cerebrospinal fluid (CSF) examination if an inflammatory aetiology is suspected and in some cases neurophysiological testing with EMG, NCS and central motor conduction time (CMCT).

Brain

Damage to supraspinal structures can produce a variety of motor signs and symptoms. Involvement is most commonly seen in cerebrovascular accidents (CVAs) with involvement of all the descending motor pathways from the cortex to the brainstem and spinal cord. This gives rise to contralateral hemiparesis with UMN signs.
If the left hemisphere is involved there is typically major disturbance in speech. Occasionally, damage is restricted to the motor cortex, when the patient may present with focal motor seizures such as Jacksonian epilepsy. The mainstay
of investigation of supraspinal motor abnormalities is MRI and/or computed tomography (CT), and CSF examination if an inflammatory aetiology is suspected. In some cases genetic testing is helpful.

Other sites commonly involved in disease processes

Basal ganglia

This produces either a slowness of movement such as in Parkinson’s disease; an abnormality of limb posture and movement (dystonia) or the development of uncontrollable involuntary movements such as chorea and hemiballismus.

Cerebellum

This produces incoordination of movement with slurred speech and abnormal eye movements. The disease processes
that typically affect this part of the CNS are multiple sclerosis, drugs such as anticonvulsants and alcohol along with a series of rare genetic conditions called the spinocerebellar ataxias (SCAs). It can also be involved by tumour growth in
which case the situation may be complicated by the development of hydrocephalus through compression of the fourth ventricle and its outflow foramina.

Did you know?

The longest paper ever published in the famous neurology journal Brain was by Kinnier Wilson in 1912 and described Wilson’s disease. It was 212 pages long!

Eye movements

The accurate control of eye movements involves a number of different structures, from the extraocular muscles to the frontal cortex, and failure to achieve this control results symptomatically in either double vision (diplopia), blurred vision or oscillopsia (perception of an oscillating image or environmental movement).
In clinical practice, disruption of the final pathway from the oculomotor nuclei (third, fourth and sixth cranial nerves) to the extraocular muscle represents one of the major causes of diplopia (e.g. myasthenia gravis), as does inflammation (e.g. multiple sclerosis) in the medial longitudinal fasciculus (MLF) pathway linking the oculomotor nuclei.

Types of eye movement

There are three major types of eye movement.

• Smooth pursuit or the following of a target accurately – which is controlled primarily by posterior parts of the cortex in conjunction with the cerebellum.
• Saccadic eye movements – where there is a sudden shift of the eyes to a new target and which are controlled by more anterior cortical areas, the basal ganglia and superior colliculi in the midbrain.
• Sustained gaze – where the eyes are fixed in one direction and which is primarily a function of the brainstem (especially the paramedian pontine reticular formation [PPRF] and rostral interstitial nucleus of the MLF).
  Eye movements, like the motor system in general, can be either voluntary (when the command comes from the frontal eye field) or reflex (when the command originates from subcortical structures and posterior parietal cortex).
  Manifestations of disordered eye movement include a loss of conjugate movements; broken pursuit movements; inaccurate saccades; gaze palsies; and nystagmus. Nystagmus is defined as a biphasic ocular oscillation containing an abnormal slow and corrective fast phase, the latter defining the direction of the nystagmus.

Anatomy and physiology of central nervous system control of eye movements

• The frontal eye fields (FEF; predominantly Brodmann’s area 8) are found anterior to the premotor cortex (PMC).
  Stimulation of this structure produces eye movements, typically saccades, to the contralateral side, and may be seen clinically in some epileptic patients.
  Damage to this area reduces the ability to look to the contralateral side so the patient tends to look towards the side of the lesion. The FEF primarily receives from the posterior parietal cortex and projects to the superior colliculus, other brainstem centres and the basal ganglia.
• The posterior parietal cortex (corresponds to Brodmann’s area 7 in monkeys) contains a large number of neurones responsive to complex visual stimuli, as well as coding for some visually guided eye movements. It is especially important in the generation of saccades to objects of visual significance via its connections with the FEF and superior colliculus.
  Damage to this area, in addition to causing deficiencies in visual attention and saccades to objects in the contralateral hemifield, can impair smooth pursuit eye movements as evidenced by loss of the optokinetic reflex. This is a reflex in which the eyes fixate by a series of rapid movements on a moving target, such as a rotating drum, with vertical lines as fixation targets.
• The primary visual cortex and its associated extrastriate areas are involved in both saccadic and smooth pursuit eye movements. Their role in saccadic movements is primarily through the projection of V1 to the superior colliculus, while the role in smooth pursuit is via extrastriate area V5, and projections to the FEF, posterior parietal cortex and pons.
  Damage to the striate and extrastriate areas, in addition to producing field defects and specific deficiencies of visual function, can also cause major abnormalities in smooth pursuit eye movements.
• The basal ganglia have a major role in the control of saccadic eye movements. The caudate nucleus receives
  from the FEF and projects via the SNr to the superior colliculus.
  Abnormalities in saccadic eye movements are seen clinically in a number of basal ganglia disorders. For example, in Parkinson’s disease the saccadic eye movements tend to be slightly inaccurate with undershooting to the target (hypometric saccades).
• The superior colliculus in the midbrain is important in the accurate execution of saccades. The cerebellum and vestibular nuclei have important complex inputs into the brainstem oculomotor system and are especially important in the control of pursuit movements, as well as mediating the vestibulo-ocular reflex.
  Damage to the cerebellum and vestibular system causes broken pursuit eye movements, inaccurate saccades and nystagmus.
• The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) is important in the control of vertical saccades and vertical gaze (both up- and downgaze) and receives important inputs from the FEF and superior colliculus while projecting to all the oculomotor nuclei.
  Damage to this structure or disruption of its afferent inputs therefore produces deficiencies in both these eye movements, and this can occur in a number of conditions including some neurodegenerative diseases.
• The PPRF receives from the FEF, superior colliculus and cerebellum and is responsible for horizontal saccades and gaze. It is thought that this structure may work in conjunction with another pontine nucleus, the nucleus raphé interpositus. This latter nucleus contains omnipause neurones, which normally exert tonic inhibition on the burst neurones of the PPRF (and riMLF) mediating the saccadic impulse.
  Damage to nucleus raphé interpositus results in random chaotic eye movements or opsoclonus. In contrast, damage to the PPRF causes deficiencies in saccadic eye movements as well as ipsilateral gaze paresis.
• The MLF mediates conjugate eye movements through interconnections between all the oculomotor nuclei and is commonly affected in some diseases of the central nervous system (CNS) such as multiple sclerosis.
  A lesion in this structure causes an internuclear ophthalmoplegia, with nystagmus in the abducting eye and slowed or absent adduction in the other eye.

Did you know?

The human eye can make up to 420 saccades per minute or eight per second.

Neurochemical disorders I: affective disorders

‘Affect’ refers to mood and affective disorders comprise of both a pathological lowering (depression) and elevation (mania) of mood.
Bipolar affective disorder (manic-depression) refers to an oscillation between depression and mania. These conditions are not simply characterized by mood changes, however, and depression may comprise a number of characteristic features.
Both depression and mania may be accompanied by features of psychosis (delusions and hallucinations). The
nature of the psychosis tends to be mood-congruent: in depression, the patient may believe that he or she is guilty of something or hear voices that are critical and unpleasant. Mania may be accompanied by grandiose delusions.

Depression

Aetiology

This is a common and mania disorder with a lifetime prevalence that has been estimated to be as high as 15%, with women affected more than men (approximately 2:1). It can occur in response to adverse circumstances (reactive depression), as well as for no apparent circumstantial reason (endogenous depression), although often the distinction between these two different types of depression is not that clear-cut. In both cases the depression probably arises through a combination of genetic and environmental factors.

• Genetic: while a number of genes have been implicated in affective disorders, specific genes for depression have not been identified, so it is thought to have a polygenic component – which is maybe more significant in patients with bipolar disorders.
• Environmental and psychological factors are also extremely important. Background personality factors have been implicated as have social stressors, which have been hypothesized to produce depression by inducing in individuals a sense that they have no personal control over events in their lives (akin to learned helplessness in rats). This basic psychological model has been extended and superseded by the view that ‘depressive cognitions’ are fundamental to depression. That is, because an individual holds specific beliefs and attributional styles, he or she may be more vulnerable to the development of a depressive illness. This view is central to the emerging use of cognitive therapies in depression.

Neurochemical basis of depression

The monoamine theory of depression suggests that the illness is caused by reduced monoamine transmission. It derives from the observation that the tricyclic antidepressants – remarkably effective in the treatment of the illness – upregulate monaminergic transmission. However, the direct evidence for monoamine disturbance in depression is scant and inconsistent.
The serotonin hypothesis suggests that depression is linked to reduced serotoninergic function and gains support from the antidepressant efficacy of the newer generation of treatments: the selective serotonin reuptake inhibitors (SSRIs). Furthermore, temporary depletion of tryptophan (a precursor of serotonin) levels causes a transient but profound resurgence of depressive symptoms in people who have been successfully treated with SSRIs and in people with a depressive illness in remission.

Cognition in depression

Depression is associated with impairments or changes in performance on a number of tests of cognitive function. Memory deficits are prominent and occur across memory domains (working memory and episodic memory) and across modalities (verbal and visuospatial). Psychomotor retardation is also common with depressed people showing an apparent lack of motivation and marked slowing of speech and motor functions, the latter manifest in generally slowed reaction times.
Sustained attention may be poor, as may planning and problem-solving.
Interestingly, some of the changes in memory and attention are characterized by an interaction with the emotional nature of test material. For example, patients may preferentially remember or attend to stimuli that have negative connotations. They may also be more likely to perceive neutral stimuli as being emotionally negative.

Treatment

A number of different therapies are employed for the treatment of depression, including psychotherapy and electroconvulsive therapy (ECT); however, the most commonly used approach is with antidepressant drugs. Most of the drugs used in the treatment of depression inhibit the reuptake of noradrenaline (norepinephrine) and/or serotonin (5-hydroxytryptamine [5-HT]). Less commonly used drugs are monoamine oxidase inhibitors (MAOIs). Because both uptake inhibitors and MAOIs increase the amount of noradrenaline and/or 5-HT in the synaptic cleft and so enhance the action of these transmitters, it has been argued that depression resulted from an ‘underactivity’ of these monoaminergic systems (see above). In mania and bipolar affective disorders lithium has a mood-stabilizing action. Lithium salts have a low therapeutic: toxic ratio and adverse effects are common. Carbamazepine valproate and lamotrigine also have mood-stabilizing actions and can be used in cases of non-response or intolerance to lithium. The
mechanisms involved in the mood-stabilizing effects of these drugs are unknown.

Amine uptake inhibitors

Tricyclic antidepressants (e.g. imipramine, amitriptyline) have proven antidepressant actions but no one drug has greater efficacy.
The choice of drug is determined by the most acceptable or desired side effects. For example, some have sedative actions (e.g. amitriptyline, dosulepin) and are more useful for agitated and anxious patients. Withdrawn and apathetic
patients may benefit from less sedative drugs (e.g. imipramine, lofepramine). In addition to blocking amine uptake, the tricyclics block muscarinic receptors, -adrenoreceptors and H1 histamine receptors. These actions frequently cause dry mouth, blurred vision, constipation, urinary retention, tachycardia and postural hypotension. In overdosage, the anticholinergic activity and a quinidine-like action may cause cardiac arrhythmias and sudden death (cardiotoxicity).
Some newer drugs (serotonin-noradrenaline reuptake inhibitors), e.g. venlafaxine, inhibit the reuptake of serotonin and noradrenaline but lack the antimuscarinic and sedative effects of the tricyclics.
Drugs that selectively inhibit serotonin re-uptake (SSRIs) (e.g. fluoxetine) are less sedative, do not have the troublesome autonomic side effects of the tricyclics and are safer in overdoses.
However, they have their own spectrum of adverse effects, the most common being nausea, vomiting, diarrhoea and constipation. They may also cause sexual dysfunction.

Monoamine oxidase inhibitors

The older MAOIs (e.g. phenelzine) are irreversible non-selective inhibitors of monoamine oxidase. Their efficacy is similar to that of the tricyclics. They are rarely used now because of their adverse effects (postural hypotension, dizziness, anticholinergic effects and liver damage). Also there may be potentially serious interactions with sympathomimetic amines (e.g. ephedrine), often present in cough mixtures and decongestive medicines, or food containing tyramine (e.g. game, cheese). Tyramine is normally metabolized by MAO in the liver. If the enzyme is inhibited, the tyramine enters the circulation and displaces noradrenaline from sympathetic nerve terminals. This may cause severe hypertension and even stroke.
Moclobemide is a newer drug that selectively inhibits MAOA and lacks most of the unwanted effects of non-selective MAOIs.

Atypical antidepressants

These drugs have little, if any, effect on serotonin or noradrenaline reuptake and do not inhibit MAO. Mirtazapine and trazodone are sedative antidepressants but have few autonomic effects. Because they are less cardiotoxic than the tricyclics, they are less dangerous in overdosage.

Did you know?

Winston Churchill used the term ‘Black Dog’ to describe his bouts of depression.

Neurochemical disorders II: schizophrenia

Schizophrenia is a syndrome characterized by specific psychological manifestations, including auditory hallucinations, delusions, thought disorders and behavioural disturbances. It is a common disorder with a lifetime prevalence of 1% and an incidence of 2–4 new cases per year per 10 000 population. It is more common in men and typically presents early in life. Like all psychiatric disorders there is no diagnostic test for this condition, which is defined by the existence of key symptoms.

• Positive symptoms:
  − delusions: abnormal or irrational beliefs, held with great conviction and out of keeping with an individual’s sociocultural background;
  − hallucinations: perceptions in the absence of stimuli.
• Negative symptoms:
  − blunting of mood, apparent apathy, lack of spontaneous speech and action;
  − disordered speech.

Aetiology

A distinction used to be made between type 1 and 2 schizophrenia but this has fallen out of fashion as it may relate more to the length of time that the individual has had the condition. The cause of schizophrenia is unknown but a number of aetiological factors have been suggested:

• Genetic factors: first-degree relatives of people with schizophrenia have a greatly increased risk of developing the disease; around 10% for siblings, 6% for parents and 13% for children. Concordance rates in twins are relatively high with figures varying from 42% to 50% for monozygotic twins and between 0 and 14% for dizygotic twins. Recent Genome Wide Association Studies (GWAS) have also confirmed a genetic basis for the condition.
• Environmental factors: e.g. infections during pregnancy also may have a role, with adoption studies demonstrating the importance of both genetic and environmental factors. In these studies gene–environment interactions have been demonstrated in children of schizophrenic parents adopted into good versus disturbed adoptive families. In this latter respect one influential theory relating to a family cause appeals to high levels of ‘expressed emotion’ (hostility, lack of emotional warmth, over-involvement) as a risk for relapse.

The dopamine hypothesis of schizophrenia

Basic model

Simply stated, this embodies the idea that schizophrenia is caused by up-regulation of activity in the mesolimbic dopamine system. The evidence for this theory comes from:

• Dopamine-blocking drugs show an antipsychotic effect.
• Drugs that up-regulate dopamine can produce positive symptoms of psychosis (e.g. amphetamines).
• Some neuroimaging studies in patients have found evidence of dopamine up-regulation.
  The dopamine hypothesis has been criticized for the lack of direct evidence in its favour and for certain inconsistencies:
• Dopamine agonists do not produce all of the symptoms of schizophrenia (notably, they do not produce negative symptoms);
• Dopamine-blocking drugs do not act immediately – there may be a long period before symptoms begin to resolve.

Revised model

The above inconsistencies led to the revision that both dopamine up-regulation and down-regulation must be invoked to account for the core features of schizophrenia, with the positive symptoms arising from up-regulation of mesolimbic dopamine function and the negative symptoms from down-regulation of mesocortical function.
However, many still think this as an inadequate explanation of such a complex disorder, and there is a view that schizophrenia is associated with N-methyl-D-aspartate (NMDA) (glutamate) receptor hypofunction. This arose from observations that NMDA blockers such as phencyclidine (‘Angel Dust’) and ketamine (widely used in anaesthesia) produce a psychotic state (including negative symptoms) that is held to be more strongly redolent of schizophrenia than the psychosis produced by dopaminergic agents. Therefore, it has been proposed that glutamate hypofunction may account for both up-regulation of the mesolimbic dopamine system, from a diminished excitatory drive of GABAergic inhibition (i.e. an attenuation of the ‘brake’ system), and down-regulation of the mesocortical system because of diminished direct drive (the ‘activating’ system).

Cognition in schizophrenia

Whilst schizophrenia is traditionally described in terms of psychotic symptoms, there is increasing evidence of cognitive deficits, particularly in the memory domain, that may accompany (and perhaps precede) the onset of these symptoms.

Treatment

The mainstay of therapy in schizophrenia remains the use of drugs that block dopamine receptors, of which there are at least five subtypes in the brain (D1–D5 receptors). These agents (e.g. chlorpromazine) are called antipsychotics or neuroleptics.
Most neuroleptics block D1 receptors but there is a close correlation between the clinical dose of antipsychotic drugs and their affinity for D2 receptors, suggesting that blockade of this receptor subtype may be particularly important. D2 receptors are found in the limbic system and in the basal ganglia, and D3 and D4 receptors are found mainly in the limbic areas.
Antipsychotic drugs (eg chlorpromazine, haloperidol) require several weeks to control the symptoms of schizophrenia and most patients require maintenance treatment for many years. Relapses are common even in drug-maintained patients. Unfortunately, neuroleptics also block dopamine D2 receptors in the basal ganglia, often producing distressing and disabling movement disorders (e.g. parkinsonism, acute dystonic reactions, akathisia [motor restlessness] and tardive dyskinesia [orofacial and trunk movements]) which may be irreversible). Blockade
of D2 receptors in the pituitary gland causes an increase in prolactin release and endocrine effects (e.g. gynaecomastia, galactorrhoea. Many neuroleptics also block muscarinic receptors (causing dry mouth, blurred vision, constipation), –
adrenoceptors (postural hypotension) and histamine H1 receptors (sedation).

Atypical drugs

Some newer drugs have a reduced tendency to cause movement disorders and are referred to as atypical agents (e.g. clozapine, risperidone, olanzapine, quetiapine). With the possible exception of clozapine, these drugs are not more efficacious than the older antipsychotic drugs. Clozapine is restricted to patients resistant to other drugs because it causes neutropenia or agranulocytosis in about 4% of patients. Risperidone and other newer atypical agents are increasingly used in the treatment of schizophrenia because they are more acceptable to patients.
It is not clear why some neuroleptics are ‘atypical’. Clozapine may be atypical because in addition to being a dopamine D2 antagonist it is a potent blocker of 5-HT2 receptors.

Did you know?

There is great debate as to whether Joan of Arc had schizophrenia, given her hallucinations and obstinate belief and the age at which this started in her.

Neurochemical disorders III: anxiety

Anxiety is a normal emotional reaction to threatening or potentially threatening situations, and is accompanied by sympathetic overactivity. In anxiety disorders the patient experiences anxiety that is disproportionate to the stimulus, and sometimes in the absence of any obvious stimulus. There is no organic basis for anxiety disorders, the symptoms resulting from overactivity of the brain areas involved in ‘normal’ anxiety. Psychiatric disorders that occur without any known brain pathology are called neuroses.
Anxiety disorders are subdivided into four main types: generalized anxiety disorder, panic disorder, stress reactions and phobias.
Many transmitters seem to be involved in the neural mechanisms of anxiety, the evidence being especially strong for γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT). Because intravenous injections of cholecystokinin (CCK4) into humans cause the symptoms of panic it has been suggested that abnormalities in different transmitter systems might be involved in particular types of anxiety disorder. This remains to be seen.
There is some evidence for decreased GABA binding in the left temporal pole, an area concerned with experiencing and controlling fear and anxiety.
There may be disturbances of serotoninergic and noradrenergic transmission in anxiety. Thus, chlorophenylpiperazine (a nonspecific 5-HT1 and 5-HT2 agonist) increased anxiety in patients with a generalized anxiety disorder. These patients also show a reduced growth hormone response to clonidine (an α2-receptor agonist) suggesting a decrease in α2-receptor sensitivity. This response is also seen in patients with major depression. This is perhaps not surprising because genetic studies suggest that generalized anxiety disorder and major depression may have a common genetic basis and both disorders benefit from the administration of antidepressant drugs.
Treatment of mild anxiety disorders may only require simple supportive psychotherapy, but in severe anxiety anxiolytic drugs given for a short period are useful. The benzodiazepines (e.g. diazepam) produce their effects by enhancing GABA-mediated inhibition in many of the brain areas involved in anxiety, including the raphé nucleus. Some antidepressants (e.g. amitriptyline, paroxetine) have anxiolytic activity and they are used for the long-term treatment of anxiety disorders. Their mechanism of action in anxiety is unclear.
β-adrenoceptor antagonists have a limited use in the treatment of situational anxiety (e.g. in musicians) where palpitations and tremor are the main symptoms. Efforts to discover non-sedative anxiolytics have led to the trial of several drugs that act on specific 5-HT receptors but only one, buspirone, has been introduced.

Anxiety disorders

• Generalized anxiety disorders have both psychological and physical symptoms. The psychological symptoms include a feeling of fearful anticipation, difficulty in concentrating, irritability and repetitive worrying thoughts that are often linked to awareness of sympathetic overactivity.
• Phobic anxiety disorders have the same core symptoms as generalized anxiety disorders but occur only under certain circumstances, e.g. the appearance of a spider (arachnophobia).
• In contrast, panic attacks are episodic attacks of anxiety in which physical symptoms predominate (e.g. choking, palpitations, chest pain, sweating, trembling).

Treatment

Benzodiazepines

Benzodiazepines (e.g. diazepam) are orally active central depressants that induce sleep when given in high doses at night and provide sedation and reduce anxiety when given in divided doses during the day. They also have anticonvulsant activity, are muscle relaxants and produce amnesia.
All these actions are brought about by the potentiation of the action of GABA on the GABAA receptor, which consists of five subunits.
Benzodiazepines enhance the action of synaptically released GABA by binding to a benzodiazepine receptor site on the GABAA receptor complex. This causes a conformational change to the GABA binding site, increasing its affinity for GABA.
The main adverse effects of the benzodiazepines are drowsiness, impaired alertness, agitation and ataxia. In anxiety disorders, benzodiazepines should only be given for a maximum of 2–3 weeks because longer treatment risks the development of dependence. If this occurs, stopping the drug frequently leads to a withdrawal syndrome characterized by anxiety, tremor, sweating and insomnia – symptoms similar to the original complaint.

Sites of action of benzodiazepines in the brain

In general, limbic and brainstem structures seem important in mediating the anxiolytic actions of these drugs. In humans, cerebral blood flow and glucose metabolism studies using positron emission tomography (PET) have not revealed consistent differences in anxious and non-anxious subjects.

Buspirone

Serotonin (5-HT) cell bodies are located in the raphé nucleus of the midbrain and project to many areas of the brain including those thought to be important in anxiety (hippocampus, amygdala, frontal cortex). In rats, lesions of the raphé nucleus produce anxiolytic effects, while stimulation of 5-HT1A autoreceptors with agonists such as 8-hydroxy-DPAT produce anxiogenic effects. A role for 5-HT in anxiety was strengthened when it was found that benzodiazepines reduce the turnover of 5-HT in the brain and, when microinjected into the raphé nucleus, reduce the rate of neuronal firing and produce an anxiolytic effect. However, stimulation of postsynaptic 5-HT1A receptors in limbic areas has anxiogenic effects. These opposing pre- and postsynaptic actions may explain why buspirone, a 5-HT1A partial agonist, has limited efficacy and works only after several weeks.

β-blockers

The evidence for the role of noradrenaline (norepinephrine) in anxiety is much less compelling than that for GABA and 5-HT.
Nevertheless, β-adrenoceptor antagonists (e.g. propranolol) have a limited use in the treatment of patients with mild or transient anxiety and where autonomic symptoms such as palpitations and tremor are the most troublesome symptoms. The beneficial effects of β-blockers in these patients may result from a peripheral action because those (e.g. practolol) that do not pass the blood–brain barrier are equally effective.

Peptides and anxiety

Several neuropeptides have been implicated in anxiety. The strongest evidence is for the anxiogenic effect of corticotrophin-releasing hormone (CRH), and CRH has also been implicated in depression.
This raises the theoretical possibility that a CRH receptor-1 antagonist may have anxiolytic actions and such drugs are under development.
Substance P may also have anxiogenic effects and an NK1 receptor antagonist is in clinical trials for anxiety and depression.
Cholecystokinin (CCK) is a gut peptide that is also present in many areas of the brainstem and midbrain and is involved in emotion, mood and arousal. Because CCK4 is one of the few agents (CO2 is another) that elicits genuine panic-like attacks, it was hoped that CCK antagonists would be useful anxiolytics. Unfortunately, clinical trials revealed that non-peptide CCK antagonists are ineffective in anxiety disorders.

Did you know?

Nitrous oxide can alleviate anxiety and carbon dioxide provokes it.

Neurodegenerative disorders

Neurodegenerative disorders are those conditions in which the primary pathological event is a progressive loss of populations of CNS neurones over time. However, it is increasingly being recognized that most neurodegenerative disorders have an inflammatory component to them, and that inflammatory diseases of the central nervous system (CNS) (such as multiple sclerosis) will cause neuronal loss and degeneration.

Aetiology

There are a number of theories on the aetiology of neurodegenerative disorders, which may not be mutually exclusive. Of late there has been much work looking at the genetic risk factors for developing these disorders, and some common sets of genes are being found for them, e.g. genes involved with inflammation and immunity.

An infective disorder

Neuronal death with a glial reaction (gliosis) is commonly seen in infective disorders (typically viral) with inflammation in the CNS.
However, in neurodegenerative disorders such a reaction is not seen, although the observation that human immunodeficiency virus (HIV) infection can cause a dementia has raised the possibility that some neurodegenerative disorders may be caused by a retroviral infection. Furthermore, the development of dementia with spongiform changes throughout the brain in response to the proliferation of abnormal prion proteins as occurs in Creutzfeldt–Jakob disease has further fuelled the debate on an infective aetiology in some neurodegenerative disorders (eg α-synuclein in PD).

An autoimmune process

Autoantibodies have been described in some neurodegenerative conditions, e.g. antibodies to calcium channels in motor neurone disease (MND). However, the absence of an inflammatory response would argue against this hypothesis, although neuronal degeneration with a minimal inflammatory infiltrate can be seen in the paraneoplastic syndromes as well as the more recently described autoimmune disorders targeting ion channels and receptors.

The result of excitotoxic cell death and free radical production

Excitatory amino acids are found throughout the CNS and act on a range of receptors that serve to depolarize the neurone and allow Ca2+ to influx into the cell. On entering the neurone, calcium is normally quickly buffered; if the level of excitation is great then there may be an excessive influx of Ca2+, which can lead to the production of toxic free radicals and cell death.
Indeed it may even be that the problem lies within the glia and their failure to buffer glutamate. This has been postulated to occur in MND. Furthermore in some cases of familial MND there is a loss of one of the free radical scavenger molecules – superoxide dismutase and in Parkinson’s disease, deficiency in complex I activity of the mitochondrial respiratory chain in the substantia nigra, both of which may lead to the overproduction of free radicals.

The ingestion or production of a neurotoxin

Many toxins can induce degenerative conditions (e.g. parkinsonism with manganese poisoning) but no such exogenous compound has consistently been found to cause any of the major neurodegenerative disorders.
Dementia of the Alzheimer type (DAT), is associated with the development of neurofibrillary tangles (NFTs) and senile neuritic plaques (SNPs) in the parahippocampal and parietotemporal cortical areas. The density of NFTs correlates well with the cognitive state of the patient. NFTs contain paired helical filaments made up of an abnormal form of the microtubule-associated protein tau – a protein that normally serves to maintain the neuronal cytoskeleton
and maintain normal axonal transport.
Thus, abnormalities in axonal transport may underlie some neurodegenerative conditions, either as a direct consequence of abnormalities in tau or proteins associated with it. In contrast, SNPs contain abnormal forms of the protein “-amyloid, derived from the ubiquitously expressed membrane-bound glycoprotein amyloid precursor protein (APP).
The reason as to why these abnormal proteins are produced and in what order is not clear – certainly some of the rare familial forms of DAT have genetic defects that influence the production of the amyloid protein (although there are rare forms of frontotemporal dementia with parkinsonism that also result from tau mutations). Whatever the reason for the development of these abnormal proteins, the result is cortical cell death. This leads to a secondary loss in the cholinergic innervation of the cortex with an associated atrophy of the cholinergic neurones in the basal forebrain, which has prompted clinical studies in the use of drugs that potentiate CNS cholinergic transmission (donepezil, rivastigmine and galantamine). These drugs are inhibitors of acetylcholinesterase in the brain. They have been shown in clinical trials to be of some limited benefit.
Most neurodegenerative conditions have now been found to contain intracellular inclusions of abnormal protein (e.g. huntingtin in Huntington’s disease, tau in some complex parkinsonian conditions, α-synuclein in Parkinson’s disease and multiple system atrophy), and may all induce disruption of the ubiquitin–proteosome system (UPS) or the autophagic lysosomal degradation pathway. These systems normally serve to package up and get rid of proteins, and as such their dysfunction will affect the processing and removal of intracellular proteins and the formation of inclusion bodies.

The loss of a specific neurotrophic factor
(Or abnormal axonal transport of substances – see above.)

Neurones are maintained by the production of a specific growth or neurotrophic factor, and the loss of one or some of these factors may underlie the development of the various neurodegenerative disorders. Clinical trials using neurotrophic factors in patients with neurodegenerative disorders have been undertaken with some disputed success with glial cell line-derived neurotrophic factor (GDNF) in Parkinson’s disease.

The activation of programmed cell death (apoptosis)

The loss of cells in most conditions (e.g. inflammation) is by a process of necrotic cell death but all cells contain the necessary machinery to initiate their own death: programmed cell death or apoptosis. It is therefore possible that neurodegenerative disorders are caused by an inappropriate activation of this programme, possibly secondary to the loss of a neurotrophic factor.

The role of inflammation

There is increasing interest in the possibility that neurodegenerative processes in the CNS may be enhanced by local inflammatory responses, especially the microglia.

Did you know?

The novelist Iris Murdoch developed Alzheimer’s disease and one of the earliest features of this was her reduced use of vocabulary in her books, which had become apparent 10 years before she was diagnosed.

Neurophysiological disorders: epilepsy

Definition and classification of epilepsy

Epilepsy represents a transitory disturbance of the functions of the brain that develops suddenly, ceases spontaneously and can be induced by a number of different provocations. It is the most prevalent serious neurological conditions, with a peak incidence in early childhood and in the elderly.

Patients may be classified according to whether:

• the fit is generalized or partial (focal), i.e. remains within one small CNS site, e.g. temporal lobe;
• there is an impairment of consciousness (if there is then it is termed complex);
• the partial seizure causes secondary generalization.
  

Overall, 60–70% of all epileptics have no obvious cause for their seizures, and about two-thirds of all patients stop having seizures within 2–5 years of their onset, usually in the context of taking medication.

Pathogenesis of epilepsy

The aetiology of epilepsy is largely unknown, but much of the therapy used to treat this condition works by modifying either the balance between the inhibitory γ-aminobutyric acid (GABA) and excitatory glutamatergic networks within the brain or the repetitive firing potential of neurones.

The recording of the electroencephalograph (EEG) reveals that epileptic fits (ictal events) are associated with either generalized synchronous or focal spike and wave discharges, although abnormalities can be seen transiently at other
times without overt evidence of a seizure (interictal activity).

A generalized epileptic fit can take several forms but classically consists of a tonic (muscles go stiff) – clonic (jerking of limbs and body) phase followed by a period of unconsciousness. This used to be termed a grand mal seizure, but is now classified as a generalized tonic–clonic seizure. Petit mal epilepsy is now reclassified as a form of primary generalized epilepsy.

A model for the generation of an epileptic discharge is that:

1. the interictal activity corresponds to a depolarizing shift with superimposed action potentials from an assembly of neurones;

2. there follows a period of hyperpolarization as these same neurones activate local inhibitory interneurones while becoming inactivated themselves;

3. with repeated interictal spikes the period of hyperpolarization shortens and this activates a range of normally quiescent ion channels in the neurone as well as raising extracellular K+ concentrations, all of which further depolarizes the neurones;

4. if sufficient neurones are activated (and the inhibition of local GABA interneurones overcome) then synchronous discharges are produced across populations of neurones which leads to a seizure;

5. the seizure or synchronous discharge is then terminated by active processes of inhibition both within the neurone (through ion channels) and within the neuronal network by GABAergic interneuronal activity.

Although this model is useful, it is clear that different forms of epilepsy have different underlying abnormalities.

• Primary generalized epilepsy, which is associated with diffuse EEG changes, is thought to result from abnormalities in specific calcium channels in the thalamus.

• Patients with complex partial seizures of temporal lobe origin may have a small scar in the mesial temporal lobe corresponding to neuronal loss and gliosis within the hippocampus, secondary to hypoxic or ischaemic insults early in life.

Treatment of epilepsy

For most patients the treatment of epilepsy involves antiepileptic drugs. A small proportion of refractory patients benefit from a surgical approach, especially if an underlying structural lesion is identified. The most common operation is temporal lobe resection, which has a 60–70% chance of making the patient seizure free.

Tonic–clonic and partial seizures are treated mainly with oral carbamazepine, valproate, lamotrigine or topiramate. These drugs are of similar effectiveness and a single drug will control the fits in 70–80% of patients with tonic–clonic seizures, but only 30–40% of patients with partial seizures. In these poorly controlled patients, combinations of the above drugs or the addition of a second-line drug, e.g. clobazam, levetiracetam, may reduce the incidence of seizures.

Absence seizures are treated with ethosuximide, valproate or lamotrigine. Absence epilepsy occasionally continues into adult life.

Status epilepticus is defined as continuous seizures lasting at least 30 minutes or a state in which fits follow each other without consciousness being fully regained. Urgent treatment with intravenous agents is necessary, which, if unchecked, result in exhaustion and cerebral damage. Lorazepam or diazepam is used initially followed by phenytoin if necessary. If the fits are not controlled, the patient is anaesthetized with propofol or thiopental.

Mechanisms of action of anticonvulsants

Antiepileptic drugs control seizures by mechanisms that usually involve one of the following:

• enhancement of GABA-mediated inhibition (benzodiazepines, vigabatrin, phenobarbital, tiagabine)

• use-dependent blockade of sodium channels (phenytoin, carbamazepine, valproate, lamotrigine);

• inhibition of a spike generating Ca2+ current in thalamic neurones (ethosuximide, valproate and lamotrigine).

• Valproate also seems to increase GABAergic central inhibition by mechanisms that may involve stimulation of glutamic acid decarboxylase activity and/or inhibition of GABAT activity.

• Vigabatrin is an irreversible inhibitor of GABAT, which increases brain GABA levels and central GABA release.

• Tiagabine inhibits the reuptake of synaptically released GABA and therefore increases central inhibition.

• The benzodiazepines (e.g. clonazepam) and phenobarbital also increase central inhibition, but by enhancing the action of synaptically released GABA at the GABAA receptor–Cl− channel complex.

• Absence seizures involve oscillatory neuronal activity between the thalamus and cerebral cortex. This oscillation involves (T-type) Ca2+ channels in the thalamic neurones, which produce low threshold spikes and allow the cells to fire in bursts. Drugs that control absences (ethosuximide, valproate and lamotrigine) reduce this Ca2+ current.

Carbamazepine, valproate and lamotrigine are widely used because of their efficacy and well-documented but largely tolerable side effects. The advantages of sodium valproate are its relative lack of sedative effects, its wide spectrum of activity and the mild nature of its adverse effects (nausea, weight gain, bleeding tendencies, tremor and transient hair loss). The main disadvantage is that occasional idiosyncratic responses cause severe or fatal hepatic toxicity and teratogenicity. For this reason, carbamazepine or lamotrigine is often preferred.

• Lamotrigine is a relatively new drug with a broad range of efficacy and seems to be relatively safe in pregnancy.

• Phenytoin is a difficult drug to use because of its complex metabolism, such that it may take up to 20 days for the serum level to stabilize after changing the dosage. Therefore, the dosage must be increased gradually until fits are prevented, or until signs of cerebellar disturbance occur (nystagmus, ataxia, dysarthria). Other unpleasant side effects, including gum hypertrophy, acne, greasy skin, coarsening of the facial features and hirsutism.

• Phenobarbital is effective in tonic–clonic and partial seizures but is very sedative. Tolerance occurs and sudden withdrawal may precipitate status epilepticus.

• Vigabatrin, gabapentin, topiramate and levetiracetam are newer agents introduced as ‘add-on’ drugs in patients where epilepsy is not satisfactorily controlled by other antiepileptics.

• Pregabalin is a prodrug of gabapentin with greater potency.

• Ethosuximide is only effective in the treatment of absences and myoclonic seizures (brief jerky movements without loss of consciousness).

• Clonazepam is a potent benzodiazepine anticonvulsant that is effective in absence, tonic–clonic and myoclonic seizures. It is very sedative and tolerance occurs with prolonged oral administration.

Anticonvulsant therapy in pregnancy requires care because of the teratogenic potential of many of these drugs, especially valproate and phenytoin. In addition, there is concern that in utero exposure to valproate may damage neuropsychological development even in the absence of physical malformation.

Did you know?

In some patients with epilepsy, changing to a ketogenic diet can help control their seizures because this diet (which is very high in fats and low in carbohydrates) forces the body to burn fat and generate ketones, which the brain then uses for its energy source.

Neuroimmunological disorders

Central nervous system immunological network

The central nervous system (CNS) has relative immunological privilege compared with the peripheral nervous system (PNS) and most other parts of the body. The reasons for this are as follows:

• The blood–brain barrier (BBB) normally prevents most lymphocytes, macrophages and antibodies from entering the CNS.

• It has a very poorly developed lymphatic drainage system.

• There is only low level expression of major histocompatibility complex (MHC) antigens.

• There are no antigen presenting cells.

However, breakdown of the BBB can greatly alter this situation.
In the resting state some activated T lymphocytes are able to cross the BBB and circulate within the CNS. In addition, MHC expression is confined to only a few cells although the situation is different in the inflamed state. Thus, once triggered, an immune response can be amplified and propagated by the secretion of cytokines and induced MHC expression, with the opening up of the BBB. In these circumstances the microglia are thought to be important as the antigen-presenting cells and their interaction with T-helper lymphocytes is then pivotal in generating a full-blown
immunological reaction.

Recently there has been great interest in the possible role of inflammation in neurodegenerative disorders of the CNS and the extent to which this is seen simply as a reaction to the cell degeneration or as a primary contributory factor in causing the loss of these cells.

Clinical disorders of the central nervous system with an immunological basis

Multiple sclerosis

Multiple sclerosis is a common neurological disorder in which the patient characteristically presents with episodes of neurological dysfunction secondary to inflammatory lesions within the CNS. Pathologically, these lesions represent small areas of demyelination secondary to an underlying inflammatory (mainly T cell) infiltrate – the trigger and target for which is not clear. The lesions often resolve with remyelination and clinical recovery, although with time a permanent loss of myelin ensues with secondary axonal loss and the development of fixed disabilities.

To date the most successful symptomatic therapy is high-dose steroids which hastens recovery from acute relapses but does not alter the long-term disease process. Of late, though, a number of more aggressive immunotherapies with drugs that target the T cells seem to be more effective, especially if given early on in the course of the disease before there has been significant axonal loss.

Acute disseminated encephalomyelitis

This is a rare inflammatory demyelinating disease of the CNS that occurs as a complication of a number of infections and vaccinations (e.g. measles and rabies vaccination). It is a monophasic illness (unlike multiple sclerosis) characterized by widespread disseminated lesions throughout the CNS that pathologically consists of an intense perivascular infiltrate of lymphocytes and macrophages with demyelination. In some cases it is fatal. This condition resembles experimental allergic encephalomyelitis, which is a well-characterized T cell-mediated disorder against a component of myelin (probably myelin basic protein) induced by inoculating animals with a combination of sterile brain tissue and adjuvants. This disorder is often used experimentally to model multiple sclerosis.

Other immunological diseases

A number of other diseases with an immunological basis can affect the CNS and these include those diseases that primarily affect blood vessels (the vasculitides).

In addition, there is a rare group of disorders in which there is CNS dysfunction as a remote effect of a cancer, paraneoplastic syndromes. In these conditions antibodies to components of the CNS are generated, presumably triggered by the tumour, which then lead to neuronal cell death and the development of a neurological
syndrome, e.g. anti-Purkinje cell antibodies cause a profound cerebellar syndrome by the immunological removal of this cell type in the cerebellum. The exact mechanism by which these antibodies exert their effect is not known as antibodies normally do not cross the BBB, but pathologically there is often evidence of a lymphocytic infiltrate in the affected structure which implies that the antibody is capable of inducing an immune-mediated process of neuronal loss.

Finally it has been shown that a number of CNS disorders are caused by antibodies to specific ion channels or receptors – e.g. anti-K+ channel antibodies causing a limbic encephalitis or anti- N-methyl-D-aspartate (NMDA) receptor antibodies causing psychoses, a movement disorder and encephalopathy – many of which are not associated with any underlying malignancy but are primary immunological disorders. Indeed there is a growing interest in the possibility that some patients with psychiatric disorders may have an autoimmune disease targeting a receptor/ion channel.

Clinical disorders of the peripheral nervous system with an immunological basis

The PNS has fewer of the protective features of the CNS so it is more susceptible to conventional immune-mediated diseases.

• The peripheral nerve is affected by a number of immunological processes, including Guillain–Barré syndrome. In this condition there is often a preceding illness (e.g. Campylobacter jejuni or cytomegalovirus infection) that induces an immune response which then cross-reacts with components in the peripheral nerve (e.g. certain gangliosides). This then induces focal demyelination in the peripheral nerve, which prevents it from conducting action potentials normally. In time the patient usually recovers, although they may require immunotherapy with either plasma exchange or intravenous immunoglobulin. A similar condition is seen in some diseases where abnormal amounts of a component of antibodies are produced (the paraproteinaemias).

• The neuromuscular junction can be affected by immunological processes as occurs in myasthenia gravis and the Lambert–Eaton myasthenic syndrome.

• Muscles can be involved in inflammatory processes. The most common form of this is polymyositis, which is a T cell-mediated condition associated with proximal weakness and pain. In contrast, dermatomyositis is a B cell-mediated disease centred on blood vessels, which causes a painful proximal muscle weakness in association with a florid skin rash. This latter condition can represent a paraneoplastic syndrome in more elderly patients with
  tumours in the lung, breast, colon or ovary.

Did you know?

In 1890, Emil von Behring discovered that the blood of animals infected with different diseases contained chemicals that attacked the diseased cells – this observation led to the discovery of antibodies.

Neurogenetic disorders

A large number of genetic disorders involve the nervous system, and some of these have pathology confined solely to this system. Recent advances in molecular genetics have meant that many diseases of the nervous system are being redefined by their underlying genetic defect.

Three major new developments have revolutionized the role of genetic factors in the evolution of neurological disease. First, genes encoded in the maternally inherited mitochondrial genome can cause neurological disorder; Second, a number of inherited neurological disorders have as their basis an expanded trinucleotide repeat (triplet repeat disorders); Third, the ability to use sophisticated genotyping of individual cases (exome sequencing) to find novel mutations is starting to yield new insights into diseases of the nervous system.

Disorders with gene deletions

Many different disorders within the nervous system result from the loss of a single gene or part thereof. For example, hereditary neuropathy with a liability to pressure palsies, in which the patient has a tendency to develop recurrent focal entrapment neuropathiesin association with a large deletion on chromosome 17, which includes the gene coding for the peripheral myelin protein 22 (PMP 22).

Disorders with gene duplications

The duplication of a gene can, under some circumstances, cause disease. An example of this is in certain types of hereditary motor and sensory neuropathy, where the patient develops distal weakness, wasting and sensory loss in the first decades of life. In some of these cases there is duplication of part of chromosome 17, including the gene coding for PMP 22.

Disorders with gene mutations

This is the most common form of genetic defect and in these diseases there is a mutation in the gene coding for a specific enzyme or protein which results in that product failing to work normally. An example of such a situation is found in some familial forms of motor neurone disease and muscular dystrophies as well as myotonic syndromes.

Disorders showing genetic imprinting

Genetic imprinting is the differential expression of autosomal genes depending upon their parental origin. Thus, disruption of the maternal gene(s) on a certain part of chromosome 15 (15q11- q13) causes Prader–Willi syndrome (mental retardation with obesity, hypogenitalism and short stature) while disruption of the same genes from the father causes Angelman’s syndrome (a condition of severe mental retardation, cerebellar ataxia, epilepsy and craniofacial abnormalities).

Mitochondrial disorders

Mitochondria contain their own DNA and synthesize a number of the proteins in the respiratory chain responsible for oxidative phosphorylation, although the vast majority of mitochondrial proteins are encoded by nuclear DNA.

Thus, mitochondrial disorders (deletions, duplication or point mutations) can result from defects in:

• these nuclear-coded genes;

• the mitochondria genome.

However, mitochondrial DNA mutates more than 10 times as frequently as nuclear DNA and has no introns (non-coding parts of the genome), so that a random mutation will usually strike a coding DNA sequence. As mitochondria are inherited from the fertilized oocyte, disorders with point mutations in the mitochondrially coded DNA show maternal inheritance (always inherited from the mother). However, within each cell there are many mitochondria and so a given cell can contain both normal and mutant mitochondrial DNA, a situation known as heteroplasmy, and it is only when a given threshold of mutant mitochondria is reached does the disease result.

The clinical disorders associated with different defects in the mitochondrial genome are legion, and the reason why some areas are targeted in some conditions and not others is not clear.

Trinucleotide repeat disorders

A number of different disorders have now been identified that have as their major genetic defect an expanded triplet repeat, i.e. there is a large and abnormal expansion of three bases in the genome. In normal individuals triplet repeat sequences are not uncommon but once the number of repeats exceeds a certain number the disease will definitely appear.

This pathological triplet (or trinucleotide) repeat either occurs in the coding part of a gene (e.g. Huntington’s disease) or in a non-coding part of the genome (e.g. Friedreich’s ataxia). The resulting expansion either causes a loss of function (e.g. frataxin in Friedreich’s ataxia) or a new gain of function in that gene product (e.g. huntingtin in Huntington’s disease). This latter aspect is of interest as the new protein appears to have a function that is unique to it and which is critical to the evolution of the neurodegenerative process. However, the mechanism by which this protein produces selective neuronal death in specific CNS sites is not known as many of the mutant gene products are widely
expressed throughout the brain and body.

The consequence of a large unstable DNA sequence as occurs in these disorders is that the triplet repeat can increase during mitosis and meiosis, resulting in longer triplet repeat sequences (dynamic mutations). This means that the most likely time for triplet expansion is during spermatogenesis and subsequent fertilization/embryogenesis, and has two major implications. First, longer repeats tend to occur in the offspring of affected men and, second, longer repeats tend to occur in subsequent generations. This results in patients of subsequent generations presenting with earlier onset and more severe forms of the disorder – a phenomenon known as genetic anticipation as longer repeat sequences
are associated with younger onset and more severe forms of the disease.

Genome-wide association studies

In recent years the ability to look across the whole genome in populations of patients with diseases of a complex genetic basis has proved possible both technically and financially. The use of a large number of markers to cover the whole genome has identified a number of regions conveying risk in disorders of the central nervous system (CNS), such as Parkinson’s and Alzheimer’s disease. This is turn will yield new insights into the common sporadic forms of the disease, as hitherto the genetics of these disorders has largely been in the domain of rare mendelian forms of the disease.

Did you know?

The first announcement that the ‘secret of life’ (i.e. the structure of DNA) had been solved was made by Watson and Crick in the Cambridge pub ‘The Eagle’ in 1953.

Cerebrovascular disease

Definition of stroke

A stroke or cerebrovascular accident (CVA) is typically an event of sudden onset (although it can occur over hours in some patients where a major vessel is slowly thrombosing). It is due to an interruption of blood supply to an area of the central nervous system (CNS) that causes irreversible loss of tissue at the core with a penumbra of compromised tissue around the area that may still be salvageable. If the disturbance in blood flow is temporary it causes a transient ischaemic attack or TIA. This is often a harbinger of a stroke. Stroke is common and its consequences depend on
the vessel that has been occluded.

Investigation of stroke

• History and examination

• Computed tomography (CT)/magnetic resonance imaging (MRI)

• Blood tests – including full blood count, erythrocyte sedimentation rate, renal function, glucose and lipids

• Electrocardiogram (ECG) which may be repeated and prolonged if a cardiac source for the stroke is suspected

Other investigation may include an ECHO cardiogram and imaging of the blood vessels and/or a CSF examination and this depends on the type of stroke (see Table 64.1).

Rare causes of stroke

The most common causes of stroke are atherosclerosis and embolic disease from the blood vessels to the brain and the heart. The other causes are quite rare. Other syndromes that resemble stroke include mitochondrial disease, where there can be a sudden onset of neurological deficits due to problems in the mitochondria and not in the vasculature. Such events in the brain typically do not obey vascular territories when investigated with MRI for example.

Treatment of stroke

• Consider local thrombolysis if a single major vessel is involved: e.g. basilar artery/venous sinus

• Acutely (if <3–4 hours) and no contraindication thrombolysis

• Treat any risk factors eg stop smoking, lower-cholesterol etc and start aspirin/perindopril/statin

• Heparin if major venous sinus thrombosis

• Surgery, if recognizable lesion causing stroke is identified e.g. 70% carotid artery stenosis/aneurysm

• Rehabilitation therapy

Did you know?

Every year, over 6 million people worldwide die from a stroke.

Neuroradiological anatomy

The ability to better delineate the anatomy of the central nervous system (CNS) in everyday neurological practice using modern imaging techniques has increased with improvements in technology and its widespread adoption in hospitals throughout the world. The major methods for imaging the nervous system are discussed, but in general magnetic resonance imaging (MRI) is the best way to look at anatomical structure and its capacity to do this is dependent on the strength of the magnetic field that can be generated with the scanner. Most hospitals use a 1.5 Tesla (T) machine, but increasingly 3T machines are being used and for research purposes 7T scanners have been developed for human use.

While the introduction of more sophisticated MRI and computed tomography (CT) sequences has enabled us to better define the vasculature of the brain, the gold standard is still formal angiography and indeed is the only way to visualize the blood vessels in the spine if this is needed, which is rare.

MRI of the cerebral hemispheres

MRI of the cerebral hemispheres clearly reveals a large number of structures which are illustrated in Figures 65.1 to 65.5. In particular:

• The different lobes of the brain can be clearly seen although the central sulcus in the human brain lies more posteriorly than one would imagine.

• The basal ganglia structures can be seen in terms of the caudate, putamen and globus pallidum. The subthalamic nucleus and substantia nigra are harder to see, although the latter is becoming easier to recognize with newer MRI scanners.

• The thalamus and the integrity of the ventricular system.

• The major pathways running in the internal capsule and the corpus callosum.

• The visual pathways can also be clearly seen up to the optic tracts. The optic radiations cannot be seen using standard imaging paradigms. Getting clear pictures of the optic pathway can be difficult and sometimes special sequences are needed to look at it in detail if there is a high suspicion of pathology.

• Limbic system structures are much harder to see, given their location on the medial aspects of the temporal lobe. The hippocampi can usually be seen, although if volumetric loss in this structure is being sought (e.g. in cases of possible Alzheimer’s disease) then special imaging protocols should be used as it is easy to mistakenly see atrophy in this structure using standard scan sequences.

• The pituitary and its relationship to the visual pathways and hypothalamus can also be seen.

MRI of the posterior fossa

CT scans can be used to look at the gross structure of the brain, but it is unable to give much information on smaller lesions, especially within the posterior fossa. Thus MRI is the modality of choice for delineating the anatomy of the brainstem and cerebellum. MRI of the posterior fossa can reveal a number of structures (Figures 65.4–65.6):

• The major divisions of the brainstem and its connection to the cerebellum and the ventricular system as it passes through the aqueduct to the fourth ventricle.

• The different lobes and parts of the cerebellum especially the cerebellar tonsil and where it lies relative to the foramen magnum (e.g. Arnold–Chiari malformations).

• Within the brainstem itself a number of structures can normally be seen. On occasions higher-resolution scans can be undertaken to look at specific parts of the brainstem, e.g. acoustic neuromas with high-resolution CT scans through the internal auditory meati.

MRI of the spinal cord (Figure 65.7)

This is typically used to look at the integrity of the spinal cord and the spine around it, to ensure that there is no compression of the spine by lesions extrinsic to it (e.g. disc herniations) or lesions within it, such as tumours.

Vasculature of the brain (Figure 65.8)

Dye can be injected into the circulation followed by the rapid capture of images as the dye moves through the different arterial vessels before draining through the venous system. This is the best way to pick up any vascular abnormalities such as small aneurysms or arteriovenous malformations.

Did you know?

Our brain requires 20% of the entire body’s blood flow.