The next step is to attempt to arouse the patient with verbal stimuli and, if it fails, painful stimuli (Figure 14.1). One of the most useful techniques is to pinch the skin on the medial aspect of the elbows and knees between your fingernails. A normal response is abduction of the limbs away from the painful stimulus; an abnormal response is adduction of the limbs towards the painful stimulus or extension of the limbs. Before testing the response to painful stimuli in front of the family, explain to them that it is the way to test when someone is unconscious. The family should also be warned that this technique may leave bruises.

FIGURE 14.1 Methods of A applying painful stimuli to the limbs, B testing the nasal and corneal reflexes and C testing eye movements using the doll’s eye procedure

The brainstem reflexes are then examined. The region tested is shown in brackets.

• The pupil responses – the afferent pathway is the 2nd nerve; the efferent pathway is the parasympathetic pathway on the surface of the 3rd nerve (midbrain and 3rd nerve)

• Doll’s eye reflexes – spontaneous and head movement-evoked eye movements (vertical eye movements = midbrain, horizontal eye movements = pons) (Figure 14.1)

• The corneal and nasal tickle reflexes – the afferent pathway is the 5th cranial nerve; the efferent pathway is the 7th nerve (pons) (Figure 14.1)

• The gag reflex – the afferent pathway is the 9th cranial nerve; the efferent pathway is the 10th cranial nerve (medulla)

Note: This reflex is not as useful as the others because many healthy people may not have a gag reflex.

Normal pupil responses, doll’s eye testing and corneal or nasal tickle reflexes indicate that the brainstem is intact and that the cause of the coma is either in the cerebral hemispheres or due to a diffuse problem. A 3rd or 6th nerve palsy does not necessarily indicate brainstem involvement. A 3rd can occur with a hemisphere lesion with downward herniation, and a 6th can occure with raised intracranial pressure as a false localising sign.

Response to pain

If the patient abducts or withdraws the limb away from the painful stimulus applied to the medial aspect of the elbow or knee, this implies that the motor pathway is intact. On the other hand, if the patient does not withdraw the limb, but the arm or leg moves towards the painful stimulus or it straightens, this indicates that the motor pathway is damaged.

Decorticate and decerebrate rigidity are two terms used to describe certain postures that may occur in the comatose patient and were formerly thought to provide localising value, although this is now in question. Decorticate rigidity refers to flexion of the elbows and wrists and supination of the arms and was said to indicate bilateral damage above (rostral) to the midbrain; decerebrate rigidity consists of extension of the elbows and wrists with pronation of the forearms indicating damage to the motor pathways in the midbrain or lower part (caudal) of the diencephalon (thalamus and hypothalamus). Similarly, the pattern of respiration is not of great localising value. For example, the cyclic breathing with periods of apnoea referred to as Cheyne–Stokes respiration can occur with bilateral hemisphere damage or metabolic suppression of the conscious state.

The pupil responses

The response of the pupils to a bright light is one of the most important aspects of the examination (see Figure 14.2). It may be necessary to use a magnifying glass to see slight reactions. The size of the pupil and the reaction to light are used to exclude or localise pathology in or affecting the midbrain and pons of the brainstem.

FIGURE 14.2 Abnormal pupil responses in the comatose patient Reproduced from Diagnosis of Stupor and Coma. 2nd edn, by F Plum, JB Posner, 1972, FA Davis.

• Bilateral normal size (2.5–5mm) and reactive pupils:

• Essentially excludes midbrain damage

• Unilateral dilated (> 6 mm) and non-reactive pupil + contralateral weakness:

• Compression of the ipsilateral 3rd cranial nerve with herniation due a mass lesion (tumour, haemorrhage, oedema related to a cerebral infarct) in the cerebral hemisphere

• Bilateral dilated and non-reactive pupils:

• Bilateral midbrain pathology

• Bilateral small (1–2.5 mm) and reactive pupils:

• Metabolic encephalopathy or bilateral deep hemisphere lesions

• Bilateral pinpoint pupils that react to light:

• Pontine haemorrhage, narcotic or barbiturate overdose

The eye movements

In normal patients the eyes may be divergent in sleep.

• Spontaneous movements of the eyes, referred to as ‘roving eyes’, exclude damage to the midbrain and pons.

• If the eyes are deviated to one side, this is either due to an ipsilateral hemisphere lesion, where the eyes look to the side of the lesion and away from the side of the paralysis, or alternatively may indicate pontine pathology, where the eyes look away from the side of the lesion and towards the side of the paralysis or hemiparesis. One exception to this rule is that with irritating hemisphere lesions the eyes may be deviated away from the side of the lesion and towards the side of the paralysis.

• Ocular bobbing indicates bilateral pontine damage, most often seen with basilar artery thrombosis. It consists of the absence of horizontal eye movements and a characteristic brisk downward movement of both eyes and then a slow upward movement to return to the normal position.

Eyes that spontaneously deviate away from the side of the paralysis indicate a hemisphere lesion on the side opposite to the paralysis; eyes that deviate to the side of the paralysis indicate a brainstem lesion on the side opposite the paralysis.

In the absence of these spontaneous ocular signs, the brainstem can be tested using the technique referred to as the oculocephalic reflex or doll’s eye test (see Figure 14.1C).

• The head is moved rapidly horizontally and then vertically while the movement of the eyes in the opposite direction to the movement of the head is observed.

• When the head is turned to the right, the eyes deviate fully left and vice versa.

• If the eye movement is full, i.e. the eyes move in the orbits to their full extent so that no sclera can be seen, this indicates that the brainstem is intact and therefore not the site of the pathology causing the impaired consciousness.

• If the eyes fail to move, this suggests damage to the ipsilateral brain stem nuclei.

• In patients with severe depression of the conscious state due to drug overdose, the oculocephalic reflexes may be abnormal and not indicate any structural damage to the brainstem. In this latter setting the pupils would usually be of normal size and react to light, something that would not occur in destructive brainstem lesions.

More intense stimulation of the oculocephalic reflex can be produced with caloric stimulation, where either warm or cold water is used to irrigate the external ear canal (ensure that the external ear canal is not occluded by wax before performing this test). Tonic deviation of the eyes with nystagmus to the opposite side with cold water and to the same side with warm water indicates that the brainstem is intact. If the eyes fail to deviate this indicates brainstem damage.

The corneal and nasal tickle reflexes

The cornea of the eye or the nostril is stimulated using cotton wool (not tissue paper as this may damage the cornea), and reflex closure of the eyes indicates that the pons is intact. Absent reflexes may occur with hemisphere lesions, drug overdose or structural brainstem lesions and, thus, absent corneal reflexes are not particularly useful for localising the problem.

ASSESSMENT OF THE CONFUSED OR DEMENTED PATIENT

Confusion, delirium and dementia

Students often have difficulty understanding the difference between delirium and dementia because of the similar symptoms. Patients with delirium develop it quickly, become agitated, and can go in and out of consciousness over time. Delirium is usually reversible and memory problems are usually short-term. Dementia develops more gradually, and the effects on memory are more permanent.

CONFUSION AND DELIRIUM

Delirium is an acute and relatively sudden (developing over hours to days) decline in attention–focus, perception and cognition. The patient appears out of touch with their surroundings and is spontaneously producing evidence of this confusion, such as a lack of clear and orderly thought and behaviour, disorientation with muttering, restlessness, rambling and shouting (often offensively and continuously) with evidence of delusion and hallucinations. It is not synonymous with drowsiness and may occur without it. Other features of delirium can include: depression, memory problems, difficulty writing or finding words and disturbances of the sleep–wake cycle.

The International Classification of Diseases, 10th edition [2], defines delirium as:

• impairment of consciousness and attention;

• global disturbance of cognition (including illusions, hallucinations, delusions and disorientation);

• psychomotor disturbances;

• disturbance of the sleep–wake cycle;

• emotional disturbances.

There are many causes of delirium and often it is multifactorial in origin. Even after extensive investigation it is not always possible to define the particular aetiology in all patients and in such patients the delirium usually resolves spontaneously. Delirium in the absence of any clearly definable alternative explanation is not uncommon in hospital in the postoperative period following prolonged anaesthesia. Delirium occurs more commonly in patients with mild cognitive impairment and it can be precipitated by a chest or urinary tract infection, electrolyte disturbances, cardiac, liver or renal failure, drug toxicity and drug withdrawal.

It is important to review all medications, particularly those that have recently been commenced or ceased. Clinical signs of chronic liver disease and the characteristic odour on the breath referred to as ‘fetor hepaticus’ (the breath of the dead where the breath has a sweet or fecal smell related to mercaptans, ammonia and ketones) identifies patients with portal hypertension and hepatic encephalopathy. Patients with a metabolic encephalopathy due to any cause may also have an abnormality referred to as asterixis: a short, flapping tremor elicited by having the patient hold their arms out in front of them with their wrists extended. Asterixis is also seen in patients with hypercapnia (elevated carbon dioxide) and anticonvulsant overdose. A tremor together with myoclonic jerks may be seen in patients with renal failure or patients exposed to antipsychotic drugs. Delirium may also be a manifestation of hypoxia in the setting of cardiac or respiratory failure or a chest infection.

Patients with delirium should have a full workup for sepsis, including looking for fever and tachycardia, examining the chest for evidence of infection, palpating the abdomen to look for tenderness that might suggest abdominal pathology and checking for neck rigidity by flexing the neck. Check the urine with a dip stick to look for evidence of infection (protein, blood and nitrites) and request a full blood examination, ESR, CRP and urine, blood and, if appropriate, sputum cultures. In the absence of obvious infection, assessments of hepatic and renal function, blood gases and electrolytes (in particular sodium, calcium and magnesium) should be undertaken. Very rarely, delirium may be the presenting feature of meningitis or encephalitis and a lumbar puncture may be necessary.

One clue is that patients with confusion and delirium are usually restless and agitated, whereas patients with symptoms related to parietal lobe pathology are not as a rule agitated.

This is particularly so for problems in the dominant parieto-temporal lobe with fluent dysphasia, word salad, literal and verbal paraphasic errors and

It is not uncommon for patients with hemisphere lesions affecting the parietal lobes to be diagnosed with confusion or delirium.

neologisms (see Chapter 5, ‘The cerebral hemispheres and cerebellum’) or non-dominant parietal lobe lesions with patients ‘lost in space’. A quick screening examination (if the patient can cooperate) with double simultaneous stimuli in the visual fields and asking the patient to hold their arms out could detect the visual inattention and parietal drift that would alert one to focal rather than diffuse brain pathology.

MANAGEMENT of DELIRIUM

The main goal in managing delirium is keeping each patient comfortable and safe. Place the patient in a quiet, well-lit room with familiar people and objects, a visible clock and wall calendar.

Alcohol withdrawal or delirium tremens, ‘the DT’s’, is a common cause of delirium. Benzodiazepines are the treatment of choice. A meta-analysis of nine prospective controlled trials [3] concluded that sedative-hypnotic agents (diazepam, chlordiazepoxide, pentobarbital paraldehyde and barbital) are more effective than neuroleptic agents (chlorpromazine, promazine and thioridazine) in reducing duration of delirium and mortality. Adequate doses should be used to maintain light somnolence for the duration of delirium. Coupled with comprehensive supportive medical care, this approach is highly effective in preventing morbidity and mortality. In general it is best to use one drug at a time, using the minimal effective dose, increasing the dose as required and reviewing the treatment on a regular basis [4]. The atypical antipsychotics such as risperidone and olanzapine have the advantage of producing less sedation and are less likely to be associated with extrapyramidal side effects.

For patients with delirium unrelated to alcohol withdrawal, there are no randomised trials but most clinicians would follow the same principles of management used in treating patients with delirium tremens [5]. Imaging in the form of a CT or MRI scan is often performed but rarely rewarding.

DEMENTIA

Dementia is derived from the Latin ‘de-’, meaning apart or away, + ‘mens’ (genitive mentis), meaning mind. It consists of a progressive global deterioration of intellectual and cognitive function with defects in orientation, memory, intellect, judgement and affect. Dementia is often associated with depression and apathy. As cognitive function declines the patient loses the ability to be independent with regard to all activities of daily living.

There are many causes of dementia; the more common include Alzheimer’s disease (AD), vascular dementia, alcoholism and Parkinson’s disease.

Potentially treatable causes of dementia include:

• hypothyroidism

• vitamin B₁ or vitamin B₁₂ deficiency

• normal pressure hydrocephalus

• subdural haematoma

• drug intoxication

• cerebral vasculitis

• heavy metal intoxication

• brain tumours

• chronic infections or inflammation such as syphilis, meningitis related to tuberculosis, cryptococcus, sarcoidosis and the extremely rare entity of Whipple’s disease.

It is anticipated that future discoveries will lead to even more cases of treatable dementia.

Do not to miss the treatable causes of ‘dementia’.

Alzheimer’s disease: Alzheimer’s disease is the commonest cause of dementia and, at the time of writing this textbook, the definitive diagnosis still requires histopathological demonstration of sufficient numbers of amyloid plaques and neurofibrillary tangles and is therefore not usually possible in life. The risk of Alzheimer’s increases with advancing age and 20–40% of patients over the age of 85 will have Alzheimer’s disease. A positive family history is not uncommon. Patients with Down syndrome (trisomy 21) have an increased risk of Alzheimer’s disease after the age of 40.

Most patients with Alzheimer’s disease will present with the insidious onset over many years of memory impairment, particularly short-term memory. As cognitive function declines the patient develops increasing difficulties with daily activities and it is this difficulty that differentiates mild cognitive impairment from true dementia. A reversal of the sleep cycle with patients sleeping during the day and wandering at night is not uncommon. Some patients with Alzheimer’s disease are unaware of their cognitive impairment and it is concerned relatives that urge them to seek medical attention. Patients may cope well in their home environment, but often the dementia is unmasked when they are admitted to hospital or when they travel and are placed in an unfamiliar environment. As the disease relentlessly progresses, patients become lost when they go for walks or when they are driving, and they have difficulty with finances, housekeeping, shopping and following instructions. Leaving the stove on is a common complaint. Walking becomes difficult and patients may develop a characteristic disorder of gait referred to as the apraxic gait (see Chapter 13, ‘Abnormal movements and difficulty walking due to central nervous system problems’). Language function deteriorates with difficulty naming objects, comprehension and then subsequently the development of aphasia. In advanced Alzheimer’s patients are no longer able to care for themselves in terms of dressing, bathing and feeding and eventually lose control of bladder and bowels.

Depression can present with many of the clinical features of dementia that resolve with treatment of the depression and this is referred to as ‘pseudodementia’. It is the intellectual impairment in patients with a primary psychiatric disorder, in which the features of intellectual abnormality resemble, at least in part, those of a neuropathologically induced cognitive deficit. These patients often complain of memory disturbance and yet are often able to recant the history of their ‘cognitive decline’ without much difficulty. The correct diagnosis may only reveal itself when the patient improves with treatment for depression. Reynolds et al [6] in a small study found that significantly greater pretreatment early morning awakening, higher ratings of psychological anxiety and more severe impairment of libido were features of pseudodementia whereas patients with dementia showed significantly more disorientation to time, greater difficulty finding their way about familiar streets or indoors and more impairment with dressing.

In very rare instances dementia may begin with focal neurological deficits [7–10] and a number of syndromes have been identified, such as posterior cortical atrophy (PCA), corticobasal syndrome (CBS), behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) (or a mixed aphasia) and semantic dementia (SD). In some instances these patients will have the pathological features of Alzheimer’s disease. These focal syndromes may remain pure for many years before the subsequent appearance of other signs of dementia. The underlying neuropathology does not uniquely associate the clinical syndromes with distinctive patterns of pathological markers. A detailed discussion of these entities is beyond the scope of this textbook [7, 9, 10].

Rapidly progressive dementia (RPD): Rapidly progressive dementias can develop subacutely over months, weeks or even days and be quickly fatal. Prion disease (Creutzfeldt–Jakob disease) is the commonest cause, but some cases of frontotemporal dementia (FTD), corticobasal degeneration (CBD), Alzheimer’s disease, dementia with Lewy bodies (DLB) and progressive supranuclear palsy may sometimes present in a fulminant form with death occurring in less than 3 years [11].

Antibody-mediated limbic encephalitis (LE) associated with cancer (paraneoplastic) or occurring without cancer (non-paraneoplastic) and Hashimoto’s encephalopathy (HE) with associated antineuronal antibodies are potentially treatable causes of RPD. Multiple sclerosis and neurosarcoidosis may also cause rapidly progressive dementia.

Limbic encephalitis presents with rapid memory loss, depression, anxiety and changes in personality followed by impaired cognitive function and seizures. Anti-neuronal antibodies may be found in the serum or cerebrospinal fluid and hyponatraemia due to the syndrome of inappropriate anti-diuretic hormone secretion may also be present.

Creutzfeldt–Jakob disease (CJD) presents with cerebellar ataxia and behavioural disturbances in addition to the rapid dementia. There is a variant form of vCJD, ‘mad-cow disease’, where the initial manifestations are major psychiatric symptoms with the ataxia and dementia associated with chorea and myoclonus occurring later in the course.

Forgetfulness or early dementia: Forgetfulness or absent-mindedness is a feature of the ageing process. Most patients over the age of 70 complain of problems with memory and many patients seek medical attention concerned about the possibility of dementia. It can be very difficult in the early stages to differentiate between these two processes [12]. Episodic memory loss precedes widespread cognitive decline in early AD [13].

DIAGNOSIS and MANAGEMENT of ALZHEIMER’S DISEASE

Magnetic resonance imaging including volumetric studies can detect specific changes in patients with minimal cognitive disturbance that may predict progression to dementia [14].

Apo E was the first gene demonstrated to increase the risk of Alzheimer’s disease and a point mutation in APP results in the early onset of Alzheimer’s disease that is inherited in an autosomal dominant pattern. Presenelin-1 on chromosome 14 and presenelin-2 on chromosome 1 have been associated with extremely rare instances of familial Alzheimer’s disease of early onset.

There are a number of cholinesterase inhibitors that provide symptomatic benefit and may decrease the rate of cognitive decline in the first few years. The management of patients with Alzheimer’s disease is predominantly providing support for the family and the patient, treatment of depression and treatment of seizures if they occur. In the early stages patients can be instructed to write lists or put up little reminders where they will see them of what they need to do that day. It is also helpful if patients with Alzheimer’s develop a daily routine including physical exercise. Caring for patients with Alzheimer’s disease is very demanding day in and day out, and organising a period of family relief where the patient is admitted to an interim care facility while the supportive family member has a break will often enable the patient to remain at home for a longer period of time.