chapter 36 Neurology
INTRODUCTION AND OVERVIEW
This chapter discusses the more common neurological symptoms and disorders encountered in general practice, and some of the less-common classic neurological problems that are rarely seen in general practice. It is far from comprehensive—more detailed information can be found in textbooks of neurology.1,2
HEADACHE
Headache is probably one of the most common reasons for a patient to consult a general practitioner (GP). Many patients are fearful that they may have a serious neurological disorder, such as a brain tumour, whereas in reality this is rare. In primary care, the risk of brain tumour with a headache presentation is less than 0.1%.3 The most common causes of headache seen by a GP are primary headaches such as those associated with fever, tension headache and, less often, migraine. The challenge for the GP is to identify the very rare but more sinister causes of headache, such as subarachnoid haemorrhage (SAH), brain tumour, cranial arteritis, meningitis and so on. There are some clinical features that should increase the suspicion of a secondary cause for headache, such as:
HISTORY
Investigations rarely elucidate the cause of headache; it is the history that is used to determine the aetiology of the headache in the great majority of patients. It has been said that if you only have 30 minutes, spend 29 on the history. Ascertain whether this headache is the first that the patient has experienced or whether it is a recurrent headache; if the latter, ask whether this headache is identical to all the others. If so, it is not unreasonable to treat for that same diagnosis. In patients presenting with new-onset headache, the single most important question is, ‘From the moment you first noticed the headache, how long did it take to reach its maximum severity?’ Headache of sudden onset should be regarded as possible SAH until proved otherwise, although with many of the other causes, sudden-onset headache such as cough, benign sex and exertional headache, there are often other clues to the diagnosis (see below). Ascertain whether there were any associated systemic symptoms such as fever, sweats, anorexia or weight loss, and, in the elderly, the presence of scalp tenderness, jaw claudication of proximal muscle, aches and pains (polymyalgia rheumatica), to alert one to the possibility of infection or cranial arteritis. Headache associated with or exacerbated by particular neck movements may point to a cervicogenic musculoskeletal cause.
In patients with focal neurological symptoms, determine whether these developed suddenly or slowly. If slowly, determine whether there was a cumulative neurological deficit or the focal neurological symptoms evolved gradually, with the latter symptoms appearing after the initial symptoms had either partly or completely resolved—a characteristic of migraine.
EXAMINATION
Every patient presenting with headache should be examined for papilloedema and neck stiffness. In elderly patients, the temporal and occipital arteries should be checked for thrombosis. If the patient has had systemic symptoms, the temperature should be checked and a detailed general examination should be performed.
INVESTIGATIONS
A computerised tomography (CT) scan rarely demonstrates any abnormality in most patients presenting to the GP with headache, and yet it is often difficult not to perform in order to reassure the patient that they do not have a brain tumour. A routine CT scan does not routinely examine the pituitary fossa, cavernous sinus, posterior fossa, region of the foramen magnum or cerebral venous system, and disorders in these sites, although very rare, can be missed by a CT scan. Magnetic resonance imaging (MRI) is the modality of choice in these circumstances. In patients with an SAH, a normal CT in the first few hours largely but not always excludes the diagnosis, and in patients with suspected SAH a lumbar puncture (LP) is necessary. An LP should also be performed in patients with suspected meningitis. Perform a full blood examination (FBE), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) if there is a suspicion of an infective illness or a systemic problem, or if the patient is elderly.
MANAGEMENT
Apart from symptomatic relief with analgesia, the management is cause-specific and is discussed below.
Headache of sudden onset
Subarachnoid haemorrhage
The diagnosis should be SAH until proved otherwise, because of the potentially disastrous outcome in patients who suffer a recurrent haemorrhage. The headache is maximum in intensity at onset and in general persists for hours (although the warning or ‘sentinel’ headache representing a less severe rupture of the aneurysm may be so brief that the patient may not consult a medical practitioner). It is usually generalised but may be predominantly occipital or frontal. There is usually nausea and vomiting and, if severe, depression of the conscious state. A focal deficit may occur if haemorrhage also occurs into the parenchyma. The general practice management consists of immediate referral to hospital for assessment. In hospital, management will consist of stabilisation and resuscitation of the patient if necessary, assessment using investigations such as CT and angiography, analgesia and then, possibly, surgery to prevent re-bleed.
Exertional and benign sex headache
It is important to remember that SAH can also occur under these circumstances. In general, patients with these headaches often have a slight warning before the onset of the explosive headache, and this continues with the activity and may resolve if the patient interrupts the exercise or sexual activity. The headache is usually brief, lasting a matter of minutes, and is not associated with nausea or focal neurological symptoms. Men are often too embarrassed to admit that the headache occurred during masturbation and it may be necessary to ask them directly. These headaches often resolve spontaneously with the passage of time, and simple reassurance is often all that is required. If treatment is requested, indomethacin 25–100 mg per day, other non-steroidal anti-inflammatory drugs or a beta-blocker may be employed.
Cough headache
A sudden brief headache may occur with coughing or straining (valsalva). This headache is brief and not associated with any other symptoms. Cough headache is another of the so-called indomethacin-responsive headaches.
Thunderclap headache
This is a syndrome consisting of shortlived headache, sudden and explosive in onset. The CT scan and LP are normal and the aetiology is unclear.
Ice-cream headache
This is the onset of sudden severe headache while eating something very cold. The headache is brief and not associated with any other symptoms, and typically occurs when the cold substance touches the palate.
Ice-pick headache
Ice-pick headache is another sudden-onset headache. It lasts only a matter of seconds but may recur. The pain is very localised, as if being stabbed with an ice-pick or a nail, most commonly in the temple, and there may be a mirror image focus of pain on the opposite side of the head. It is more common in patients with migraine and is another of the indomethacin-responsive syndromes.
Tension headache and chronic daily headache
This is the most common type of headache encountered by the GP. The headache can be generalised, or focal, unilateral or bilateral. Focal neurological symptoms, nausea and systemic symptoms are absent. The headache typically commences some time after awakening and lasts most of the day, and fluctuation in severity during the day is characteristic. The patient may retire with the headache but usually awakens in the morning free of headache. Chronic daily headache is by definition the presence of headaches on a daily basis for six or more months. Although worsening of daily headache is regarded as a ‘red flag’ for a possible more sinister secondary cause of headache, in fact worsening in terms of increased duration and intensity of headache is not uncommon in these patients, particularly in the setting of increased use of analgesics, a syndrome referred to as the ‘analgesic overuse syndrome’. This is a vicious cycle, where increasing use of analgesics (even aspirin or paracetamol) leads to increasing severe headaches, leading to the use of even more of analgesia. A clue is that the patient often states: ‘I am taking all these pain killers and they do not seem to work any more.’ Many patients also have neck discomfort and when examined may have tenderness in the trapezius and sternocleidomastoid muscles; this often leads to a diagnosis of cervicogenic headache. Here the headache is assumed to be arising from disease in the cervical spine, and yet most patients do not have any demonstrable pathology on imaging or have osteoarthritis that may be an incidental finding, particularly in older patients where it is often present and asymptomatic. Relief of headache can be seen after massage to the neck muscles, physiotherapy or chiropractic, but the benefit may be short-term only.
A multifaceted approach to the treatment of tension-type headache, employing psychological, physiological and pharmacological therapies is recommended.4 The treatment for the analgesic overuse syndrome is for the patient to withdraw analgesia, which they often find difficult. The use of a tricyclic antidepressant for a short period has been shown to be beneficial.5
Migraine
Migraine is a complex headache disorder that has many manifestations. The aetiology is unknown. Patients experience recurrent headaches occasionally associated with recognisable precipitating factors. The diagnosis is entirely dependent on the history of the headache and associated features if present, as currently there are no tests to confirm the diagnosis. The patient with ‘classic migraine’ rarely presents a diagnostic problem. The headache is preceded by visual phenomena or neurological symptoms, referred to as the aura, that commence in one part of the body or visual field and spread, over a period of minutes (on average lasting approximately 30 minutes). The headache is usually throbbing in nature, and commences after the onset of the aura and increases in severity over minutes to hours. It is almost invariably associated with nausea, vomiting, photophobia and phonophobia. The headache persists for hours to days. The associated visual symptoms can vary from photopsia (positive phenomena such as flashing lights or bright dots) to patches of loss of vision, referred to as scotomata, that may or may not be surrounded by positive visual phenomena or fortification spectra. The diagnosis is more difficult in patients with recurrent headaches in which gastrointestinal, visual and neurological symptoms are absent. The diagnosis of probable migraine can be made if the patient experiences recurrent headaches that persist for hours on end and are either present on awakening or awaken the patient from their sleep. Rare forms of migraine include hemiplegic migraine and basilar artery migraine. Some patients can experience the aura of a migraine without the subsequent development of a headache, referred to ‘migraine without headache’ or ‘migraine equivalents’. Migraine headaches that occur only at the time of menstruation are referred to as ‘menstrual migraine’ and are due to the drop in the oestradiol level just prior to menstruation (see ch 52, Gynaecology).
Once a headache has started, rest in a quiet, darkened room and ensure adequate fluid intake. A combination of magnesium, feverfew and riboflavin can be helpful at the onset of a headache. Several well-designed trials support the effectiveness of spinal manipulation therapy in the treatment of migraine headaches.
In essence, treatment consists of selecting a drug with a potential side-effect profile the patient is willing to contemplate, commencing with the smallest possible dose and increasing up to the minimal required or maximal tolerated dose. Often it is a matter of trial and error.
Initial standard medical treatment often consists of simple analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs) with an antiemetic drug such as prochlorperazine or metoclopramide. Ergot preparations, oral, rectal and subcutaneous, or the triptans, have all been shown to be effective.6,7
INTEGRATIVE MANAGEMENT OF HEADACHE/MIGRAINE
Prevention
The goals of prevention are to reduce the frequency, severity and duration of attacks, and to reduce disability.
Triggers
Ask the patient to keep a headache diary to identify triggers. Include date and time. Record food, events, exercise and amount of sleep in the previous 24 hours, and significant life stressors.
Lifestyle
Diet
An elimination–rechallenge diet may help identify triggers. Dietary triggers include chocolate, cheese, monosodium glutamate, tyramine (in aged cheese, red wine, smoked fish, figs), nuts, citrus, dairy and preserved meats (nitrates).
Avoiding smoking, caffeine and alcohol will reduce headache frequency and severity for many patients.
Ensure adequate fluid intake and maintain regular meal times.
Herbs and supplements
Magnesium
Intracellular magnesium levels are often lower in people with migraine headaches and magnesium deficiency is common. Two randomised controlled trials (RCTs)8,9 found that high-dose magnesium reduced the frequency and duration of migraine headaches. Magnesium can also help prevent migraine in women with cyclic headaches related to periods, and is also used in treatment of conditions involving muscle spasm or tension, fibromyalgia, anxiety states and tension headaches.
Riboflavin (vitamin B2)
Regular riboflavin may help reduce the frequency and shorten the duration of migraine headaches through anti-nociceptive and anti-inflammatory effects.10 Dose: 400 mg/day for at least 3 months, to assess effect in combination with feverfew and magnesium.
SAMe
In a preliminary study, SAMe reduced the frequency, intensity and duration of migraines for most patients.
Feverfew (Tanacetum parthenium)
A systematic review of six RCTs11 concluded that evidence favours feverfew as an effective preventative treatment against migraine, and that it is well tolerated. Note that there is significant variation in the amount of active ingredient in commercially available feverfew preparations.
Physical therapies
Chiropractic
In one study12 including 127 people with migraine headaches, 22% of those who received chiropractic manipulation reported more than a 90% reduction of migraines and 49% reported a significant reduction of the intensity of each episode. There is some evidence to suggest that patients with tension headache and headache related to neck pain will benefit from chiropractic, although overall the evidence is less strong that chiropractic is beneficial for migraine.13
Physiotherapy
A review article14 evaluating nine studies that tested spinal manipulative therapy for tension or migraine headaches concluded that this technique is comparable to medications used to try to prevent either of these two types of headaches.
Acupuncture
Acupuncture is well studied as an effective treatment for various types of headache. Results from a study published in 200315 suggest that having an acupuncture treatment when migraine symptoms first begin is as effective as sumatriptan. Later in the course of the migraine attack, however, the medication works better than acupuncture. A 2001 Cochrane review16 found 26 trials on acupuncture for headaches. Of these, 16 trials investigated migraine headaches, six tension-type headaches and four various headaches. The majority, although not all, showed acupuncture to be better than placebo/sham acupuncture for tension/migraine headaches, although the quality of many trials was suboptimal. A more recent literature review by Endres and colleagues17 discussed 10 trials of acupuncture for migraine and concluded that a 6-week course of acupuncture was at least not inferior to a 6-month course of prophylactic treatments, and had a role in the integrated management of migraine headaches.
Drugs for prevention
Trigeminal autonomic cephalalgias
The term ‘trigeminal autonomic cephalalgias’ refers to cluster headaches, chronic paroxysmal hemicrania and SUNCT syndrome.
Cluster headache
The pain of a cluster headache is strictly unilateral and in or around the eye, the temple, frontal or maxillary regions. The pain is excruciatingly severe and is often referred to as ‘suicide headache’. The headaches last from 15 minutes to 3 hours, with a curious periodicity, often occurring at the same time of day.
Ipsilateral reddening and watering of the eye and blockage of the nostril are characteristic. A transient Horner’s syndrome during the headache is virtually pathognomonic. It is most often seen in men. The attacks occur in bouts or clusters.
Treatment of the acute episode includes oxygen (100%), with a flow rate of at least 7 L/min over 15 minutes, and triptans such as subcutaneous or intranasal sumatriptan. Verapamil up to 240 mg/day is probably the drug of first choice for prophylaxis (maximum dose depends on efficacy or tolerability). Corticosteroids are considered effective in cluster headache, despite the lack of level I or II evidence. Methylprednisolone 100 mg per day (or equivalent corticosteroid) given orally or at up to 500 mg intravenously per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments.
Paroxysmal hemicrania
Paroxysmal hemicrania may be either episodic or chronic, and consists of paroxysmal headache attacks very similar to those observed in cluster headache, but the attacks are more frequent and of shorter duration, and lack the circadian rhythm seen with cluster headache. Complete abolition of the headaches with indomethacin is characteristic.
SUNCT syndrome
SUNCT syndrome consists of short-lasting, unilateral, neuralgiform headaches with conjunctival injection and tearing lasting between 5 seconds and 4 minutes and occuring from as few as three times per day to as often as 200 times per day. These headaches are also strictly unilateral and periorbital; they are triggered by touching the periorbital region, talking or chewing food. There is mild conjunctival injection and watering of the eye.
Lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful.
Idiopathic or benign intracranial hypertension
Idiopathic intracranial hypertension (IIH) or benign intracranial hypertension (BIH) tends to occur in obese females, but can be seen in patients of either sex who are not obese. The headaches are constant and have usually been present for weeks to months prior to presentation. They tend to be constant in nature, generalised and often worse on awakening. The diagnosis relies on the presence of papilloedema in the setting of a normal MRI scan (including magnetic resonance venography (MRV) to exclude cerebral vein thrombosis) and an elevated cerebrospinal fluid (CSF) pressure of > 20 cm H2O with normal CSF microbiology and biochemistry. Treatment includes recurrent lumbar punctures, acetazolamide and, in resistant cases, lumbo-peritoneal shunt.
Cranial arteritis
Cranial arteritis should be suspected in older patients, typically 75 years of age and older—it is rarely seen in patients under the age of 50 years. The headache is of insidious onset of days to weeks, often with systemic ill health, fever, polymyalgia rheumatica, scalp tenderness and jaw claudication, with the latter two virtually pathognomonic. The ESR is raised, often as high as 100, but may be normal early in the course of the illness, and therefore the ESR should be repeated once or twice per week when the diagnosis is suspected and the initial ESR is not raised. Occasionally the diagnosis can be made at the bedside by detecting thrombosed temporal arteries (see Fig 36.1). If the clinical suspicion is high and despite a normal ESR, the patient should be treated with high-dose corticosteroids and a temporal artery biopsy obtained as a matter of urgency. Delays in treatment can result in blindness and, less frequently, cerebral infarction.
FUNNY TURNS
Intermittent disturbances of neurological function are a very common problem and the list of potential causes is extensive. This section discusses the more common causes encountered by a GP, including syncope, Stokes-Adams attacks, epilepsy, benign positional vertigo and hyperventilation syndrome.
HISTORY
Funny turns consist of intermittent disturbances of function, and therefore the diagnosis is almost entirely dependent upon a very detailed history, as the examination is usually normal and investigations rarely reveal a diagnosis unless they are performed at the time that the patient is having an episode, and even then tests are usually normal.
It is important to obtain a detailed description of not only the circumstances under which the episode occurred, but also the time of the day and the exact nature and distribution of each and every symptom, as well as the timing of each of the individual symptoms in terms of their duration and their relationship to the development of other symptoms.
When obtaining a history, be certain to analyse what was happening immediately before the event or ‘ictus’. If there is an eyewitness or if the patient does not lose consciousness or memory, ascertain exactly what happened during the ictus, and then analyse what happened immediately after the ictus, up until the time that the patient regained normal function or behaviour.
EXAMINATION
As already stated, the examination in this situation—measurement of blood pressure lying and standing—may confirm the clinical suspicion of postural hypotension. An irregular pulse may be present in patients with symptoms related to an arrhythmia. A carotid bruit may indicate the presence of a carotid stenosis in a patient with focal cerebral ischaemia. Severe aortic stenosis or the murmur of idiopathic hypertrophic sub-aortic stenosis may be present in patients with exercise-induced syncope. In patients with posture-induced vertigo, the Hallpike manoeuvre may demonstrate the characteristic delayed onset of vertigo and nystagmus that abates with maintenance with a fixed posture. Hyperventilation—asking the patient to breathe heavily and quickly—can reproduce the symptoms of hyperventilation syndrome, but it is important to remember that hyperventilation will make anyone feel unwell, and therefore the symptoms must be reproduced exactly.
INVESTIGATIONS
The investigations already alluded to rarely, if ever, establish a diagnosis in patients with intermittent disturbances of function. If seizures are frequent or can be precipitated by sleep deprivation or hyperventilation, then video-electroencephalographic monitoring may occasionally detect a seizure (see Fig 36.2). Holter monitoring can on rare occasions detect complete heart block in patients with suspected Stokes-Adams attacks. Symptoms related to hyponatraemia, hypokalaemia or hypocalcaemia are so rare that routine electrolyte estimation is rarely helpful. A full blood examination could detect anaemia or evidence of an infection, but intermittent symptoms related to either of these entities are very rare. Imaging such as CT scan or MRI scan is usually normal, except for patients with focal seizures.
MANAGEMENT
Management is specifically related to the nature of the disturbance, and is discussed in each section below.
Syncope
Syncope is also referred to as vasovagal syncope or neurocardiogenic syncope. It occurs predominantly in teenagers and young adults. A typical episode consists of prolonged warning symptoms consisting of lightheadedness, clamminess, blurred and then darkening vision, with worsening severity of symptoms and subsequent loss of consciousness (LOC). The patient is limp and, if standing, falls to the ground with eyes closed and no abnormal movements. Pallor is common and bradycardia is present. The period of impaired consciousness is brief—a matter of minutes. An important diagnostic clue is that the patient can prevent LOC if they lie flat immediately. In most instances, reassurance and advice to lie flat immediately is all that is required.
Loss of consciousness is a symptom of a variety of conditions. First episodes of syncope need to be investigated. In older patients particularly, cardiac arrhythmias need to be excluded.
Stokes-Adams attacks
Stokes-Adams syndrome is a disorder of the elderly, although rarely it can occur in younger patients. It consists of sudden LOC without warning, brief and with no ‘post-ictal’ confusion. It relates to complete heart block, and treatment consists of insertion of a pacemaker.
Epilepsy
Epilepsy is the propensity to recurrent seizures. There are many ways to classify seizures, one common way being to divide them into generalised and partial seizures. Generalised seizures include tonic-clonic (previously referred to as grand mal), absence (petit mal), atonic and tonic. Partial seizures include simple (no loss of awareness) and complex (loss of awareness) partial seizures. Some patients experience warning symptoms as the initial manifestation of the seizure, referred to as an aura, and some patients have a period of drowsiness and confusion after the seizure, referred to as post-ictal drowsiness and confusion.
Tonic-clonic seizure
Tonic-clonic seizure may or may not be preceded by an aura. An aura suggests a focal onset. The patient stiffens and may ‘cry out’—the so-called ‘cri de chat’—the eyes remain open, and this tonic phase, lasting up to 30 seconds, is followed by the clonic phase, with repeated flexing movements of all four limbs. Tongue or cheek biting and incontinence of urine and faeces may also occur. There is a period of post-ictal drowsiness and confusion. Most episodes last less than 2–3 minutes, rarely as long as 20 minutes.19
Absence seizure
There is no warning. Suddenly the patient interrupts their behaviour and stares into space. There is often repetitive blinking, but nothing else. After 10 seconds to 1–2 minutes, the patient returns to normal as if nothing has happened. There is normally no post-ictal drowsiness or confusion.
Complex-partial seizure
Often but not invariably there is an aura. There are symptoms such as déjà vu, jamais vu, olfactory or gustatory phenomena, rarely visual or auditory hallucinations. The patient interrupts what they are doing and stares into space. Abnormal movements such as lip smacking, repetitive swallowing or fidgeting are common, and the patient is unresponsive. As opposed to absence seizures, there is a period of post-ictal drowsiness and confusion.
Diagnosis
The diagnosis is essentially a clinical one and based almost entirely on the history of the episode, as only rarely do patients have a seizure while undergoing electro-encephalography (EEG). Current recommendations advocate an EEG, CT or MRI brain scan in all patients presenting with a first unprovoked seizure. The presence of epileptic discharges on an EEG in patients with their first seizure increases the risk of recurrence. Many patients presenting with their first apparent seizure have, on detailed questioning, had unrecognised seizures in the past.20
Treatment of seizures and epilepsy
Most seizures last only a matter of 1–2, rarely 5, minutes, and the initial management is simply to prevent the patient from harming themselves and to lie them on their side when the seizure is finished. Prolonged seizures and status epilepsy require prompt intervention. Intravenous (IV) lorazepam is the drug of choice in both adults and children.21
Precipitating factors are uncommon but, when they occur, include flashing lights in patients with photosensitive epilepsy, sleep deprivation, excessive alcohol, forgetting medications and an intercurrent illness.
Choosing the correct drug for the individual patient can be complex, and is determined by the type of epilepsy and the side effect profile the patient is willing to contemplate.
Carbamazepine is the drug of choice for partial or focal seizures, and valproic acid for generalised seizures.22 However, carbamazepine interferes with the oral contraceptive pill and causes drowsiness; valproic acid can result in hair loss and obesity, side effects that young women are often not willing to contemplate. There are many guidelines23 and these are frequently evolving and should be consulted on a regular basis.
Integrative management of epilepsy
The adverse effects of antiepileptic pharmaceuticals make it difficult to attain optimal dosage levels in order to prevent seizures in many cases.24 Current evidence suggests that 25–50% of individuals with epilepsy have tried some form of CAM therapy.25–27 It is important to note that these therapies are not a substitute for medication; however, depending on the effectiveness of the intervention(s), dosage reductions under medical supervision may be possible.28
Mind–body medicine
A systematic review assessing several different meditative practices (meditation, meditative prayer, yoga, relaxation) has revealed some evidence for the efficacy of meditation in the treatment of epilepsy.29 In particular, studies have demonstrated that transcendental meditation (TM) may be a potential antiepileptic treatment. However, further trials are required, as many of the EEG recordings during TM (increased alpha, theta, gamma frequencies with increased coherence and synchrony) are similar to the neuronal activity that occurs during seizures.30
Sleep
It has long been known that there is a close relationship between the physiological state of sleep and the pathological process underlying epileptic seizures, but the connection is still not well understood.31 Sufferers of epilepsy often demonstrate multiple sleep abnormalities, such as increased sleep latency, fragmented sleep, increased awakenings and stage shifts and an increase in stages 1 and 2 of non-REM sleep.32 It is important that any sleep disorders are identified and managed as soon as possible, as sleep deprivation has been shown to increase the frequency of epileptiform discharges and seizures.33–35 Sleep quality, as well as daytime alertness and neurocognitive function, can be improved by anticonvulsant medications, ketogenic dietary principles and vagus nerve stimulation.33 However, it should be noted that poor sleep can also be an adverse effect of some anticonvulsant drugs.24,36
Sunshine
Individuals with epilepsy who have been on long-term treatment with various anticonvulsants may develop hypocalcaemia, osteomalacia and osteopenia that is independent of vitamin D metabolism. It has been demonstrated that there are regional variances in the incidence of drug-induced bone disease and this has been attributed to variances in sunlight exposure, with the majority of reports coming from areas of low sunshine or from institutionalised patients.37,38
Exercise
In times past, exercise was restricted for those with epilepsy, rather than encouraged, as it is today. As many people with epilepsy still fear suffering an exercise-induced seizure, they often lead a sedentary life and have poor physical fitness.39 Although there have been rare cases of exercise-induced seizures, both clinical and experimental data have shown that exercise can reduce the frequency of seizures as well as improving cardiovascular and psychological health.40,41 Indeed, current evidence demonstrates that regular exercise may have a moderate seizure-preventative effect in 30–40% of this population.39 Most sporting activities, including contact sports, are safe to participate in, according to current medical recommendations. Supervised water sports and swimming are also considered safe, provided seizures are well controlled. However, sports such as hang-gliding and scuba diving are not recommended, as there is a high risk of severe injury or death if a seizure were to occur.40 It is imperative that medical advice regarding exercise is individualised for each patient, taking into account their seizure type and frequency.40
Yoga
Recent studies have shown that yoga can reduce seizure index and increase quality of life in people with epilepsy.42 Yoga has also been shown to significantly improve parasympathetic parameters, suggesting that it may have a role in the treatment of autonomic dysfunction in patients with refractory epilepsy.43
Diet
Maintaining good blood sugar balance, identifying and eliminating allergenic foods and avoiding suspected triggers such as alcohol, artificial sweeteners, diet soft-drinks, energy drinks and MSG are important in the management of epilepsy.28,44,45 Growth retardation is common among children with epilepsy and this appears to be secondary to poor dietary intake. Dietary intake of vitamins D, E and K, folate, calcium, linoleic acid and alpha-linolenic acid has been found to be below the recommended daily allowance (RDA) in approximately 30% of children with intractable epilepsy.46
Studies of dietary treatments for epilepsy suggest that approximately 50% of children have a 50% reduction in seizures after 6 months. Approximately one-third will achieve more than 90% reduction in their seizures. Such diets maintain their efficacy when provided continuously for several years. Furthermore, long-term benefits may be seen even when the diet is ceased after only a few months, indicating neuroprotective effects.47 Other dietary guidelines for the management of epilepsy are given below. Recommending such diets in the management of epilepsy needs to be balanced with the overall nutritional needs and health of the patient.
Ketogenic diet
The ketogenic diet is a high-fat, low-carbohydrate, high-protein diet used to treat medically refractory epilepsy.48 At least 15–20% of patients on the ketogenic diet experience more than 50% reduction in seizure frequency. For this reason, the ketogenic diet should be considered an early treatment for drug-resistant epilepsy, not a ‘last resort’.49–51 The ketogenic diet may also be a valuable therapeutic option for children with drug-resistant focal epilepsy, particularly those with recent deterioration of seizure control.52,53
Modified Atkins diet
The modified Atkins diet is a less-restrictive ketogenic diet. It has no restrictions on calories, fluids or protein, and does not involve fasting. As for the ketogenic diet, high-fat foods are encouraged, with 10 g/day of carbohydrate allowed in children and 15 g/day in adults. Approximately 45% of patients have 50–90% seizure reduction, with 28% having more than 90% seizure reduction.54 The ketogenic diet appears to exert its effects more quickly, although by 6 months the difference is no longer considered significant.50
Low glycaemic index diet
A study in 2009 reported on the efficacy, safety and tolerability of the low glycaemic index diet in paediatric intractable epilepsy. More than 50% reduction from baseline seizure frequency was seen in 42%, 50%, 54%, 64% and 66% children at 1, 3, 6, 9 and 12 months respectively.55
Polyunsaturated fatty acids
Increased concentrations of both ketone bodies and polyunsaturated fatty acids (PUFAs) have been found in the cerebrospinal fluid and plasma of patients on the ketogenic diet, and it is thought that a high dietary intake of PUFAs may be one mechanism responsible for the potent anticonvulsant effects of the ketogenic diet.56,57 Supplementation with omega-3 fatty acids has also been shown to prevent status epilepticus-associated neuropathological changes in animal studies.58 Although PUFAs have been shown to reduce seizures in several animal models, available data regarding the effects of supplementation in epileptic patients (1–3 g EPA/DHA daily) reveal mixed results with respect to seizure frequency.59–61 More research is therefore required before PUFAs can be definitively recommended as a treatment option for epilepsy.56
Amino acids
Current research suggests that serotonin has an antiepileptic effect, and serotonin receptors are expressed in almost all networks involved in epilepsies. Some SSRIs, such as fluoxetine, have been found to improve seizure control, and some antiepileptic drugs have recently been found to increase endogenous serotonin levels.62–64
Tryptophan
Tryptophan is an essential amino acid and the only brain precursor of serotonin. It has been estimated that patients with epilepsy have approximately 30% lower brain intake of tryptophan compared with controls. Whey proteins that are high in tryptophan but lower in other large neutral amino acids are currently being trialled in combination with antiepileptic medications.62
Taurine
Taurine is one of the most abundant free amino acids found mainly in excitable tissues. Taurine is necessary for the production of GABA, one of the major inhibitory neurotransmitters in the limbic system.65 For this reason, drugs that target GABA receptors are the mainstay of treatment of seizures, with the recent transplantation of GABA-producing cells effectively reducing seizures in several well-established models.66,67
There have been multiple animal studies demonstrating that taurine-fed animals have increased levels of GABA and a higher threshold for seizure onset compared to controls.65 Furthermore, increased taurine levels in the hippocampus improve membrane stabilisation, significantly reducing neuronal cell death and favouring recovery after neuronal hyperactivity.68,69
Carnosine
Carnosine is an amino acid with many of the features of a neurotransmitter. It has the ability to act as both a neuromodulator and a neuroprotective agent, and it may indirectly influence neuronal excitability by modulating the effects of zinc and copper.70–72 Carnosine may have a significant anticonvulsant effect and, as such, it may prove to be a potential anticonvulsant treatment for epilepsy in the future.73
Antioxidants
Excessive production of free radicals with neuronal hyperexcitability have been strongly implicated in the pathogenesis of idiopathic epilepsy. There is therefore a possible role of antioxidants in combination with antiepileptic drugs for better seizure control,74–76 although, as with other chronic illnesses, it is likely that a nutritious diet rich in antioxidants such as vitamins A, C and E is likely to be far more effective than a poor diet supplemented by antioxidants. Results have thus far been mixed for vitamin E supplementation, and more studies are required before definitive recommendations can be made.77
Selenium deficiency has been implicated in the pathogenesis of epilepsy.78 Anticonvulsants may further deplete total body selenium stores, and failure to advise appropriate selenium supplementation, especially to pregnant women taking sodium valproate, may increase the risk of neural tube defects or other free radical mediated damage.79
Zinc
Altered zinc homeostasis appears to be associated with epilepsy; however, the definitive role of zinc as a neuromodulator in synapses is still uncertain.80,81
Other vitamins and minerals
Many anticonvulsant medications are known to reduce folic acid levels, subsequently raising homocysteine levels. Homocysteine, however, is known to be a convulsing agent that can result in increased seizure recurrence and intractability to medications. In addition, anticonvulsant medications can disturb lipid metabolism, creating hypercholesterolaemia, dyslipidaemia and altered uric acid metabolism. As such, routine supplementation with folic acid, vitamin B12, B6, C, E and beta-carotene for all those on anticonvulsant medications is important.82
A Cochrane review has found that vitamin B1 improves both neuropsychological and cognitive functions in patients with epilepsy. In the same review, vitamin D was also found to improve bone mineral density in those taking anticonvulsant medications.28,77
Manganese deficiency has also been associated with seizures in both animals and humans, according to a systematic review. More research is needed, as it is currently unclear as to whether this is a cause or an effect of the convulsions.83
Herbs
Herbal medicine has been used for centuries in many cultures for the treatment of epilepsy and some patients may be self-medicating with herbal medicines. It is therefore important for the GP to ask about the patient’s use of herbal preparations, as many herbs can increase the risk of seizures by affecting cytochrome-P450 enzymes and P-glycoproteins, or through possible contamination by heavy metals.84,85
Well-designed clinical trials of herbal therapies for epilepsy are scarce. However, based on animal studies and numerous anecdotal observations of clinical benefits in humans, further research is certainly warranted.84,85
The flavonoid derivatives from Scutellaria baicalensis Georgi, Artemesia herba-alba, Melissa officinalis and Salvia triloba have all been found to exert anticonvulsant effects by exhibiting significant affinity for the GABA(A) receptor benzodiazepine binding site.86,87 Ginkgo biloba appears to have the capacity to both induce and inhibit seizures.88
Interestingly, Curcumin has also recently been shown to significantly prevent generalisation of electroclinical seizure activity as well as the pathogenesis of iron-induced epileptogenesis.89,90 Further studies are required.
Various Chinese herbs, such as Chaihu-longu-muli-tang, appear to have antiepileptic properties, and it also appears that the reduction in seizure frequency may be related to the antioxidant effects of the herbs.91 Shitei-To is another TCM formulation that may have therapeutic effects in the prevention of secondarily generalised seizures. It is made from three medicinal herbs: Shitei (calyx of Diospyros kaki L.f), Shokyu (rhizome of Zingiber officinale Roscoe) and Choji (flower bud of Syzygium aromaticum).92
Prevention
Lifestyle measures that may be important in the management of epilepsy have been discussed previously. Furthermore, living as ‘cleanly’ as possible is important for individuals with epilepsy, as there are numerous documented toxic causes of seizures. These include substance abuse (alcohol and recreational drugs), exposure to various industrial and household products, occupational nickel and other heavy metals.94 Animal studies have demonstrated that blood lead levels similar to those found in humans living in urban areas with high pollution levels can lower seizure threshold.95
Research on hospital admissions of patients in status epilepticus reveals several environmental factors that are either protective or precipitative. It appears that there is a significant diurnal pattern, with the majority of admissions occurring between 4 pm and 5 pm, and least admissions in the early morning hours. Admissions also vary significantly throughout the lunar cycle, with the peak at day 3 after the new moon and trough at 3 days before the new moon. Admissions have been noted to be highest on bright, sunny days, whereas dark days, high humidity and high temperature appear to be significantly protective factors.96
Benign positional vertigo
Benign positional vertigo is a not-uncommon condition that can produce disabling attacks of shortlived vertigo precipitated by movement of the head, such as looking up, bending over, turning the head, lying down, getting out of bed or rolling over in bed. Each of these movements stimulates the semicircular canals; in this condition, there are free-moving pathological densities or crystals from the otolith that break off and enter the endolymph, producing abnormal stimulation of the delicate hair cells floating in the fluid. The diagnosis is confirmed by the Hallpike manoeuvre and treatment is by the Epley manoeuvre. Descriptions of how to perform these can be readily obtained from the internet.
Hyperventilation syndrome
Hyperventilation syndrome is a disorder that is frequently missed by the GP. Patients present with lightheadedness (not vertigo) that fluctuates in severity and can persist for minutes to hours. There is often dryness of the mouth and an inability to take a big breath (rather than shortness of breath) and a sense of tightness in the chest. When severe, there can be peri-oral and peripheral paraesthesia in the hands and feet, which occurs without loss of function and at times may be unilateral. The condition can be diagnosed by asking the patient to take deep breaths, in and out, for several minutes—this will reproduce their symptoms. Traditionally, patients have been advised to breath in and out of a paper bag, but this is impractical. The problem is simply resolved by the patient holding their breath in expiration for 20 seconds, taking a breath, breathing out and holding it for another 20 seconds—this is repeated until the symptoms resolve.
MOTOR WEAKNESS
HISTORY
The presence of weakness indicates a lesion somewhere between the motor cortex in the frontal lobe and the relevant muscle group on the contralateral side, with the motor pathways crossing at the level of the foramen magnum. The rapidity of onset of weakness, the pattern of weakness and the presence or absence of significant wasting and/or fasciculations should be elucidated in the history. An enquiry should be made as to the presence of a family history of any disorder causing weakness, as a number of disorders of muscle are familial. The presence of sensory symptoms excludes the anterior horn cell, the motor nerve root, the neuromuscular junction and muscle as the site of the pathology.
EXAMINATION
Central nervous system (CNS) causes of weakness produce a classic ‘upper motor neuron’ pattern of weakness with finger extension, shoulder abduction and elbow extension in the upper limbs and hip flexion, weakness of dorsiflexion of the feet and knee flexion in the lower limbs. This pattern of weakness would most often be associated with increased tone (with or without clonus), increased reflexes and up-going plantar responses. If the facial muscles are affected with CNS, then the forehead is not affected. In disorders of the peripheral nervous system (PNS), the pattern of weakness will indicate whether the problem is in the anterior horn cell (usually associated with significant wasting and fasciculations), motor nerve root (usually associated with significant radicular pain), plexus, peripheral nerve, neuromuscular junction (fluctuating weakness with exercise) or muscle. The presence of sensory signs excludes disorders of the anterior horn cell, motor nerve root, neuromuscular junction or muscle. In disorders of the PNS, the tone may be normal or decreased, the reflexes are often absent, plantar responses are down-going and, if present, sensory signs will reflect the site of the problem in the PNS. Disorders of muscle are usually associated with preserved reflexes (rare exceptions to this include myotonic dystrophy and inclusion body myositis). If the weakness affects the face, it is important to see whether the muscles that wrinkle the forehead (frontalis muscle) are affected; if so, this points to a lower motor neuron facial palsy. If the forehead is not affected but there is weakness around the mouth, this is an upper motor neuron facial weakness.
INVESTIGATIONS
Magnetic resonance imaging, with its ability to image the spinal cord, brainstem and cerebral hemispheres, has revolutionised the assessment of patients with weakness related to the CNS. It is also superior to computerised tomography at imaging the nerve roots and plexuses. Other tests inlcude creatine kinase (CK), nerve conduction studies (NCS), electromyography (EMG) and muscle biopsy for disorders of muscle. It is also useful to conduct nerve conduction studies for disorders of nerves, in particular individual nerves involved in entrapment syndromes (carpal tunnel syndrome at the wrist, tardy ulnar palsy at the elbow or common peroneal nerve compression at the neck of the fibula), peripheral neuropathy and disorders at the neuromuscular junction where single-fibre EMG (SFEMG) is useful. The cerebrospinal fluid (CSF) may provide vital clues in both CNS and PNS disorders.
MANAGEMENT
Management is disease specific and is discussed below.
Paraplegia
The term paraplegia refers to bilateral leg weakness. The most likely causes include spinal cord pathology (resulting in upper motor neuron signs) such as transverse myelitis (sometimes the presenting symptom of multiple sclerosis) or spinal cord compression secondary to spinal cord trauma, malignant vertebral metastases or benign intraspinal tumours. A useful clinical point is that a thoracic cord lesion in a middle-aged to elderly female is a meningioma until proved otherwise. Bilateral leg weakness may also result from PNS problems such as a peripheral neuropathy or even disorders of muscle. Diabetic amyotrophy and lumbosacral neuritis can result in severe pain in the thighs and hip region, and proximal weakness with absent knee reflexes in one or both thighs, evolving over days to weeks.
Monoplegia
Weakness confined to one limb, if it affects the entire limb, is more likely to be central in origin, particularly if it has evolved rapidly. Focal weakness in a limb is more likely to be related to a nerve root or individual nerve, but can also occur with CNS problems. A not-uncommon presentation in general practice is hand weakness, related to either an ulnar nerve lesion or a C8-T1 radiculopathy. In the latter, both the medial and lateral heads of flexor digitorum profundus (FDP) are affected, causing weakness of flexion of the distal phalanges of all four fingers, whereas in an ulnar nerve lesion the lateral two digits are spared (this part of FDP is supplied by the median nerve). The sensory loss will involve the medial two digits and medial aspect of the palm in both conditions, but will be more extensive and up the medial aspect of the forearm in a radiculopathy. Another common presentation is the wrist drop or ‘Saturday night palsy’, with radial nerve compression in the radial groove causing weakness of wrist and finger extension, weakness of elbow flexion in semi-supination (brachioradialis) but sparing of the triceps. There is often a small area of altered sensation at the base of the thumb. This is a self-limiting condition.
Hemiparesis/hemiplegia
Hemiparesis refers to partial weakness down one side of the body, whereas hemiplegia refers to a total loss of strength down one side of the body. Weakness affecting the arm and leg on one side is most likely related to a lesion on the opposite side of the brain, above the level of the foramen magnum where the motor pathway crosses, although a lesion in the upper cervical spinal cord on the same side as the weakness cannot be excluded. Weakness affecting the face, arm and leg on one side clearly points to a lesion affecting the motor pathway above the facial nerve nucleus situated in the pons.
Facial weakness
The most common cause of an upper motor neuron facial weakness would be cerebral ischaemia on the contralateral side. Bell’s palsy is the most common cause of a lower motor neuron weakness.
Bell’s palsy
Bell’s palsy is an acute, idiopathic, unilateral, lower-motor-neuron facial-nerve paralysis of uncertain aetiology. It is one of the most common ‘urgent’ referrals to a neurologist, because most patients fear that they have suffered a stroke. Patients may often complain of paraesthesia on the face; more often they present with the gradual onset of weakness afflicting one side of the face (bilateral cases are rare but do occur) that develops over hours to days. The inability to wrinkle the forehead on the same side confirms that the weakness relates to a lower motor neuron problem. The presence of hyperacusis in the ipsilateral ear and altered taste on the ipsilateral side of the tongue (related to involvement of the chorda tympani) when present are pathognomonic for Bell’s palsy. Facial and corneal sensation are not affected. The condition resolves spontaneously in more than 80–90% of patients.
Corticosteroids and aciclovir have been recommended in the belief that functional outcome is improved.97 However, a 2009 Cochrane review concluded that corticosteroids and aciclovir have not been proved to be beneficial.98 Subsequent to this review, a large randomised controlled trial99 demonstrated complete recovery at 3 months in 83% of patients treated with prednisolone (50 mg per day for 10 days), as opposed to 63.6% for patients treated with placebo. At 9 months, 94.4% of the prednisolone-treated group had completely resolved, compared to 81.6% for the placebo. No benefit was found from aciclovir.
Acute and chronic inflammatory demyelinating neuropathy
The term acute inflammatory demyelinating neuropathy (AIDP) has replaced the term (Landry) Guillain-Barré (Strohl) syndrome. This presents with the rapid onset of weakness usually affecting the limbs, with proximal weakness in the lower limbs and distal weakness in the upper limbs initially, subsequently becoming generalised weakness of the limbs. There is almost invariably neck flexion and occasionally neck extension weakness. The cranial nerves may also be affected, resulting in bilateral facial weakness, palatal weakness or weakness of the extra ocular muscles, resulting in variable patterns including a pseudo-internuclear ophthalmoplegia (INO). The reflexes are absent and there may or may not be peripheral sensory loss. Some patients develop involvement of the autonomic nervous system, resulting in arrythmias, periods of hypertension and hypotension and disturbances of bladder and bowel function. The respiratory muscles are involved in severe cases, and patients will often require long-term ventilation. In addition to supportive measures, either intravenous immunoglobulin (IVIG) or plasma exchange is used in the acute phase.100–102 IVIG is probably the treatment modality of choice, for ease of use. The prognosis is variable, with approximately 75% of patients making an excellent recovery; the remainder have mild or moderate impairment, with severe disability occurring in less than 5% of patients.
Chronic inflammatory demyelinating neuropathy (CIDP) can cause the same patterns of weakness as AIDP but evolves more slowly (by definition over more than 6 weeks). IVIG or corticosteroids should be considered in sensory and motor CIDP. IVIG should be considered as the initial treatment in pure motor CIDP.103
Motor neuron disease
Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), presents with weakness and fatigue associated with significant muscle wasting and fasciculations in the absence of any sensory symptoms. Muscle cramps can occur. Four distinct clinical phenotypes have been identified, with different rates of progression and survival. Patients presenting with global involvement have the worst prognosis, while patients presenting with a flail arm survive longer.104 When MND affects the bulbar musculature, patients present with a characteristic dysarthria, with wasting and fasciculations of the tongue. At present there is no specific treatment, but these patients should be cared for in specialised centres with expertise in MND.
Myasthenia gravis
Myasthenia gravis is a very rare autoimmune disease and most GPs are not likely to see a case. The characteristic feature is a weakness that is exacerbated by use of the muscle and reduced in intensity by rest. Myasthenia gravis can remain confined to the extra ocular muscles, where it presents with intermittent ptosis and variable horizontal and vertical diplopia—for example, when reading or watching television. Myasthenia affecting muscles in the rest of the body is referred to as generalised myasthenia. Myasthenia affecting the bulbar musculature (the lower four cranial nerves) will present with dysarthria exacerbated by talking, dysphagia and difficulty chewing, exacerbated by eating. When it affects the muscles of the arms and legs, patients will complain of increasing weakness when they are trying to do activities such as hanging the washing on the line or washing their hair, or they may complain of increased difficulty walking, and of having to rest. The diagnosis can be made at the bedside by asking the patient to repeatedly exercise and by demonstrating increased weakness; or, if it affects the extra ocular muscles, by asking the patient to look up, and observing increased ptosis and the development of increasing diplopia, the longer the patient is looking up. Applying ice to the ptosed eyelid can lead to a dramatic resolution of the ptosis.105 Another bedside test is the Tensilon test, where edrophonium hydrochloride is injected and a transient improvement or resolution of symptoms can be observed. The ice test and the Tensilon test both have a high sensitivity (92–95%) and specificity (97%). Antibodies directed against the acetylcholine receptor (ACHR) are highly specific (98%) but the sensitivity varies from one report to another, from as low as 54% to as high as 88%.106 Electrodiagnostic studies include repetitive nerve stimulation, where a decremental response is observed and the variability of stimulation of the acetylcholine receptor by acetylcholine can be observed with single fibre electromyography (SFEMG)—this is referred to as increased jitter. All patients with myasthenia gravis should have a CT scan of the chest to look for thymic hyperplasia (usually seen in younger patients) or a thymoma (in older patients); these can be either benign or locally malignant. Ocular myasthenia gravis sometimes responds to the cholinesterase inhibitor pyridostigmine.107 Thymectomy is recommended for patients with thymic hyperplasia108 or thymoma.109 IVIG is very effective in the treatment of myasthenic crisis and can be used preoperatively prior to thymectomy or prior to any surgery in patients with generalised myasthenia gravis.101 Corticosteroids, other immunosuppressive agents and plasma exchange are used in patients who fail to respond to thymectomy.110,111
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