Cervical cord compression (see Figure 13.2) can be seen in younger patients with congenitally narrow spinal canals (10–13 mm). The spinal cord is stretched during flexion of the cervical spine and buckling of the ligamentum flavum occurs during extension of the cervical spine. Thus, repeated flexion and extension in the patient with significant canal narrowing may cause intermittent acute compression of the spinal cord, and it is thought that this may also account for the clinical deterioration seen in many cases of CSM [1].

FIGURE 13.2 MRI scan of A normal cervical spine and B spinal cord compression due to cervical spondylosis

The natural course of CSM for any given individual is variable and precise prognostication is not possible. Once moderate signs and symptoms develop, however, patients are less likely to spontaneously improve. Worsening occurs more commonly in older patients whereas patients with mild disability are less likely to worsen [1].

CSM can present in a variety of ways.

1. The commonest presentation is with the insidious onset of difficulty walking related to weakness and/or stiffness (due to spasticity). Some patients will have neck pain from the cervical spondylosis; pain in the arm related to nerve root compression is less common.

2. Older patients in particular may present with weakness and wasting of the small muscles of the hands related to nerve root compression, and the signs of spinal cord compression are noted when they are examined.

3. A presentation that is much less common is the central cord syndrome resulting from a hyperextension injury in the setting of cervical canal stenosis where the weakness is greater in the upper than the lower limbs with or without a suspended sensory loss (affecting the shoulders and upper torso like a cape) and urinary retention.

4. Patients with cervical cord compression may experience an electric shock-like ensation radiating down their back or into their limbs with neck flexion, the so-called L’Hermitte phenomena commonly seen in patients with multiple sclerosis (MS).

The examination will reveal someone who may walk with a stiff-legged gait if there is associated spasticity, the tone will be increased with or without sustained ankle clonus, the knee reflexes will be abnormally brisk; ankle reflexes are often absent in the elderly and this should not exclude consideration of cervical cord compression. The plantar should be up-going but this is not universal.

Some elderly patients assume that the gradual onset of difficulty walking is simply the result of advancing age and tend not to seek medical attention until the cord compression and limb weakness are severe.

MANAGEMENT of CERVICAL SPONDYLOTIC MYELOPATHY

Investigations

• A plain X-ray of the cervical spine may demonstrate degenerative disease, but this is common in elderly patients in the absence of cervical cord compression.

• Magnetic resonance imaging (MRI) is currently the imaging modality of choice in patients suspected of having cervical cord compression.

Treatment

There are no prospective randomised controlled trials comparing medical management with surgery for CSM. The choice of therapy will be dictated by the patient’s attitude to surgery, the severity of the cervical cord compression and the fitness from the medical point of view of the patient to undergo surgery. Patients are advised that the goal of surgery is to prevent worsening and that improvement cannot be guaranteed, although many patients do in fact improve following appropriate surgery. Many neurosurgeons would recommend a period of observation in patients with mild symptoms and signs, but it would seem reasonable to recommend surgery for patients with moderate disability. Once moderate signs and symptoms develop, however, patients are less likely to spontaneously improve and such patients should consider surgical decompression.

Thoracic cord compression: Thoracic spinal cord compression most commonly occurs with metastatic malignancy, less commonly with a thoracic disc, epidural abscess or extrinsic spinal cord tumour such as a meningioma or a neurofibroma. There is an aphorism that ‘a thoracic cord lesion in a middle-aged to elderly female is a meningioma (benign tumour arising from the meninges) until proven otherwise’. Back pain is rare with a meningioma, more common but not a universal feature of thoracic discs, but increasingly severe back pain occurs for on average 8 weeks or longer in 80–95% of patients who subsequently develop malignant cord compression [2]. Patients who are not known to suffer from malignancy, but who develop increasingly severe midline (especially thoracic) back pain, should be investigated promptly in the hope of preventing malignant cord compression.

Although initially the pain is localised to the vertebra, subsequent nerve root compression can result in radicular pain. The back pain is often worse after lying down and this can be a vital clue. Rapidly developing weakness in the legs is the initial and dominant neurological symptom once malignant spinal cord compression occurs; sensory symptoms are less common and sphincter disturbance occurs late. A delay in the diagnosis of malignant cord compression is common with many patients only diagnosed after they lose their ability to walk [2, 3] and, unfortunately, once significant cord compression related to malignancy occurs the prognosis for recovery is poor.

In patients with preexisting malignancy, particularly breast and prostate, the development of back pain should raise the suspicion of possible secondary malignancy in the spinal column and prompt investigation (see Figure 13.3).

FIGURE 13.3 MRI scan of A thoracic spinal cord normal (the arrow shows normal CSF around the spinal cord) and B malignant thoracic spinal cord compression (the arrow points to the malignancy; the CSF space is obliterated)

The following suggest spinal metastases:

• pain in the thoracic or cervical spine

• severe unremitting or progressive lumbar spinal pain

• spinal pain aggravated by straining

• nocturnal spinal pain preventing sleep

• localised spinal tenderness [4].

It has been recommended that patients with known malignancy should be advised to return urgently within 24 hours for review should they develop back pain in the midline [4].

Severe thoracic back pain followed by the rapid development of spinal cord compression can be the initial manifestation of malignancy in as many as one-third of patients with cancer of unknown primary origin, non-Hodgkin lymphoma, myeloma and lung cancer [2]. Metastatic disease less commonly affects the cervical or lumbar spine. Although almost any systemic cancer can metastasise to the spinal column, prostate, breast and lung are the most common [2].

Intrinsic spinal cord problems: Transverse myelitis is the commonest intrinsic cord lesion resulting in dysfunction in the lower limbs and difficulty walking in the younger patient while spinal cord ischaemia is seen in the elderly. Spinal cord ischaemia can develope abruptly or insidiously. Other intrinsic spinal cord problems such as tumours and the cavitating lesion referred to as syringomyelia are very rare and are beyond the scope of this book.

TRANSVERSE MYELITIS: Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory and autonomic dysfunction with many infectious and non-infectious causes [10].

The Transverse Myelitis Consortium Working Group [11] has established diagnostic criteria that require:

• bilateral signs and/or symptoms of spinal cord dysfunction affecting the motor, sensory and autonomic systems

• a clearly defined sensory level

• the exclusion of cord compression

• the demonstration of inflammation within the cerebrospinal fluid (CSF). If none of the inflammatory criteria is met at symptom onset, repeat MRI and lumbar puncture evaluation should be performed between 2 and 7 days following symptom onset.

The development of neurological symptoms and signs is often preceded by a febrile illness up to 4 weeks prior to onset [12], typically an upper respiratory tract infection. Patients present with an ascending sensory loss, with the development of a sensory level in the majority of patients with or without a paraparesis, paraplegia, quadriplegia and urinary retention [12, 13]. The symptoms may develop rapidly over as little as 4 hours or more slowly over several weeks.

Patients whose spinal cord symptoms reach maximal severity in < 4 hours from onset should be presumed to have an ischaemic aetiology [1].

In one study of acute transverse myelitis, a parainfectious cause was diagnosed in 38% of patients but the underlying infectious agent was identified in a minority of patients. In 36% of patients the aetiology remained uncertain and in 22% it was the first manifestation of possible MS. The MRI scan (see Figure 13.4) was abnormal in 96% of cases (i.e. a normal MRI is rare but does not exclude a diagnosis) [12].

FIGURE 13.4 MRI scan of transverse myelitis

Acute non-compressive myelopathies can also be classified according to their aetiology [14]:

1. multiple sclerosis

2. systemic disease (e.g. systemic lupus erythematosus [SLE], antiphospholipid syndrome, Sjögren’s syndrome

3. parainfectious

4. delayed radiation myelopathy

5. spinal cord infarct

6. idiopathic myelopathy.

MANAGEMENT of TRANSVERSE MYELITIS

Patients suspected of having transverse myelitis should have an MRI scan and a lumbar puncture.

The CSF is abnormal [14] with:

• mildly elevated protein (except in post-infectious myelopathy where it may exceed 1 g/L)

• lymphocytic pleocytosis (as low as 1 cell/mm³ in delayed radiation myelopathy to as high as 320 cells/mm³ in post-infectious myelopathy)

• a normal CSF glucose

• negative CSF cytology for malignant cells.

MRI scanning usually but not invariably reveals abnormalities that may be restricted to one or many spinal segments [13]. Typically the MRI signal changes extend at least three segments above the sensory level.

In western countries transverse myelitis may be the presenting feature of MS or it may manifest during the course of this disease. Patients who are ultimately diagnosed with MS are more likely to have asymmetric clinical findings, predominant sensory symptoms with relative sparing of motor systems, MRI lesions extending over fewer than two spinal segments, abnormal brain MRI and oligoclonal bands in the CSF [11]. It is important to test for oligoclonal bands in the CSF and serum to detect intrathecal synthesis seen with MS.

CONUS MEDULLARIS LESION: This chapter has discussed central nervous system causes of difficulty walking whereas the previous chapter discussed peripheral nervous system problems. There is one very rare syndrome that produces both upper and lower motor neuron signs in the lower limbs and this is a lesion at the level of the conus medullaris (the lower end of the spinal cord at the level of the 2nd lumbar vertebra) with or without the involvement of the cauda equina (the sheath of lumbosacral nerve that extends from the lower end of the spinal cord through the spinal canal exiting at the appropriate level and that looks like a horse’s tail, hence the name).

The clinical signs in a pure conus medullaris lesion consist of impaired sensation affecting the lower sacral nerve roots (S3–S5) with urinary retention and urinary or faecal incontinence. If the cauda equina is also involved there will be low back pain, weakness and sensory loss in the lower limbs that is asymmetrical, but it usually affects the lower lumbar and upper sacral nerve roots (L5–S1), resulting in foot drop and absent ankle reflexes.

Truncal ataxia occurs with hypothyroidism [19] and alcoholism [20]. Patients with isolated truncal ataxia walk with a wide-based gait with little in the way of nystagmus or ataxia in the limbs.

The commonest cause of ataxia related to cerebellar disease would be cerebellar infarction. Two less common causes of cerebellar ataxia affecting the cerebellar hemispheres are the paraneoplastic cerebellar syndrome [21] and the hereditary spinocerebellar atrophies (SCA) [22]. The paraneoplastic cerebellar syndrome may be the initial presenting symptom of malignancy or develop after the diagnosis of malignancy is established. The clinical picture is one of very disabling ataxia affecting the limbs and trunk, together with dysarthria and nystagmus evolving rapidly over days to weeks. On the other hand, the hereditary spinocerebellar atrophies present with the insidious onset of ataxia affecting the limbs with or without nystagmus and dysarthria.

Difficulty walking not sure why

There are two conditions, Parkinson’s and the apraxia of gait, where patients have increasing difficulty walking in the absence of any obvious weakness or sensory disturbance in the lower limbs or any sensation of instability in the head, and the patients are uncertain why they are having difficulty. In both conditions the patient will appear to walk with short steps: in Parkinson’s the patients shuffle while they walk whereas with the apraxia of gait the steps are short but the patient does not shuffle. It can be very difficult at times to differentiate Parkinson’s disease from the apraxic gait.

PARKINSON’S SYNDROME

Parkinson’s syndrome is a term used to describe patients with clinical features that include one or more of:

• a resting tremor

• stooped posture

• slowness of movement referred to as bradykinesia

• cogwheel rigidity (increased tone that has a sensation of the muscle giving way in little jerks).

The commonest cause of Parkinson’s syndrome is Parkinson’s disease, but drugs (such as phenothiazines, butyrophenones, metoclopramide, reserpine and tetrabenazine) may cause a reversible Parkinson’s syndrome, and toxins (such as manganese dust or carbon disulfide) and the recreational drug N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause an irreversible Parkinson’s syndrome [23] by destroying the dopamine neurons in the midbrain. The term ‘Parkinson’s disease’ is reserved for patients with the above clinical features who have the characteristic neuropathology of loss of pigmentation in the substantia nigra and the presence of the Lewy bodies.

Parkinson’s is largely a disease of the elderly, although in up to 10% of patients the onset is before the age of 50. The patient with Parkinson’s disease affecting both lower limbs walks with small shuffling steps where the sole of the shoe is often heard scraping along the ground. As the patient walks there is a lack of arm swing. They may also develop an involuntary sensation where they cannot stop themselves from walking with short accelerating steps, the so-called festinating gait. Occasionally, patients present with unilateral involvement mimicking a hemiparesis and are thought to have had a ‘stroke’. The insidious onset and the presence of tremor and cogwheel rigidity on examination should alert the clinician to the correct diagnosis.

As the Parkinson’s disease becomes more severe, patients will have difficulty getting out of bed and low chairs and will walk with a stooped posture. Patients may have a fixed expression on their face, blink infrequently and lose the ability to smile. Curiously, many patients with Parkinson’s can still dance. The other characteristic feature of Parkinson’s is the resting tremor, and this is discussed in the next section together with the principles of management of Parkinson’s.

APRAXIA OF GAIT

Apraxia of gait is an inability to walk in the absence of weakness, sensory deficit, instability or incoordination. It is a perseveration of posture and an inability to perform the serial movements necessary for ambulation. In the initial stage there is difficulty in starting to walk or changing direction. Patients walk with small steps referred to as the ‘marche a petit pas’ (walks with little steps); unlike in Parkinson’s they do not shuffle but lift their feet off the ground. The features that help differentiate apraxia of gait from Parkinson’s disease are listed in Table 13.1.

TABLE 13.1

The clinical features that help differentiate Parkinson’s from frontal lobe apraxia, two commonly confused conditions

Clinical feature	Parkinson’s	Frontal lobe apraxia
Resting tremor	Yes	No
Shuffles when walks	Yes	No
Lifts feet when walks with small steps	No	Yes
Swings arms when walking	No	Yes
Smiles spontaneously	No	Yes
Bradykinesia	Yes	Yes
Difficulty arising from chair	Yes	Yes
Grasp and palmo-mental reflexes	No^∗	Yes
Cogwheel rigidity(rigidity constant during testing)	Yes	No
Gegenhalten rigidity(rigidity increases with testing)	No	Yes

^∗May occur late in the course when cognitive decline is present.

To the inexperienced clinician these patients appear to have cogwheel rigidity but it is in fact Gegenhalten or ‘an involuntary, voluntary resistance to passive movement’. The way to differentiate between the cogwheel rigidity of Parkinson’s and the apparent cogwheel rigidity in frontal lobe disorders is that, in patients with Parkinson’s, the cogwheel rigidity is evident from the moment testing begins whereas, in patients with Gegenhalten, the increased tone that has the sensation of cogwheel rigidity is not present initially but, the more the clinician tests for increased tone, the greater the degree of resistance creating the impression of a cogwheel rigidity. If testing is momentarily interrupted by simply lowering the hand and wrist and then started again, the increased tone is not present initially but once again increases with further testing.

The method of testing tone in patients with suspected extrapyramidal or frontal lobe apraxia of gait is different from the method when one suspects altered tone due to a problem affecting the motor pathway. One passively extends and then flexes the wrist repeatedly while compressing the wrist as if you are trying to push or compact the hand into the distal aspect of the radius and ulnar. Subtle degrees of increased tone can be detected by using a technique referred to as Jendrassik’s manoeuvre, a distracting technique in which the patient simultaneously clenches the opposite fist, lifts the arm with the clenched fist in the air and shakes their head from side to side. This is a particularly useful technique when looking for alteration in tone in patients with early suspected Parkinson’s.

Note: Jendrassik’s manoeuvre is also used to overcome the voluntary suppression of reflexes or to elicit reflexes that initially appeared to be absent without reinforcement. While the attention is being diverted, the lower extremity reflexes are tested while the patient hooks the flexed fingers of the two hands together forming a ‘monkey grip’ and forcibly tries to pull them apart.

The apraxic gait, although not confined to frontal lobe pathology, is characteristic of patients with disorders of the frontal lobe, most frequently on the basis of degenerative or vascular diseases of the brain. There are several treatable causes that should always be excluded:

• communicating (‘normal pressure’) hydrocephalus [24]

• bilateral subdural haematomas

• sub-frontal meningioma.

Communicating or ‘normal pressure’ hydrocephalus: Communicating hydrocephalus is relatively rare but important because it is treatable. The diagnosis is a largely a clinical one and is based on the triad of:

• gait impairment

• mild cognitive dysfunction

• unwitting urinary incontinence.

The lateral, 3rd and 4th ventricles are enlarged with little or no atrophy of the cerebral hemispheres. It presents with a fairly rapid onset over weeks or months of gait apraxia associated with unwitting urinary incontinence and mild cognitive impairment. Patients with significant cognitive impairment who subsequently develop apraxia of gait and patients in whom the decline is very slow over years are less likely to have communicating hydrocephalus.

The term ‘normal pressure’ is a misnomer as continuous intracranial pressure monitoring has demonstrated intermittent elevation of the intracranial pressure. One theory is that there is decreased arterial blood flow into the head because of closing down of the arterioles with advancing age, resulting in less venous blood flow out and consequently less CSF resorption via the transparenchymal/transvenous route. Patients with ‘normal pressure’ hydrocephalus may already have enlarged ventricles due to decreased CSF resorption via the arachnoid granulations and villi. When the decreased absorption via the transparenchymal/transvenous route is added, this leads to increased CSF pressure, expansion of the lateral ventricles and increased shearing forces on the local white matter tracts, particularly the corticospinal tracts to the legs that are adjacent to the ventricles.

If there is an alteration in the rapidity with which a patient with Parkinson’s worsens, it is important to consider another cause. A common and readily reversible cause of a rapid deterioration in patients with Parkinson’s disease is a urinary tract infection. Worsening has also been described in patients with subdural haematoma [30]. Other

MANAGEMENT of ‘NORMAL PRESSURE’ HYDROCEPHALUS

The aetiology of normal pressure hydrocephalus is unknown. Imaging such as a CT scan of the brain demonstrates enlargement of all the ventricles.

A number of diagnostic tests designed at predicting response to ventricular shunting have been described. These include various MRI abnormalities [25], external continuous lumbar drainage [26], continuous intraventricular pressure monitoring [27] and the CSF tap test [28], where a lumbar puncture is performed and CSF is removed to see if the patient temporarily improves. None has been validated in terms of ruling out a response to surgery. The problem with ventricular-peritoneal CSF drainage is the risk of reducing the intracranial pressure too much, resulting in subdural haematomas or hygromas. This risk has been reduced in recent years with the use of adjustable pressure shunts [29].

In patients with chronic neurological diseases such as Parkinson′s, the rate of worsening tends to be fairly constant in the individual patient and, therefore, a rapid deterioration should alert the clinician to an alternative diagnosis.

examples of this principle seen by this author include spinal cord compression and dermatomyositis, which lead to a more rapid decline in the patient’s ability to walk than had occurred with their Parkinson’s disease.¹

ABNORMAL MOVEMENTS

Abnormal movements of the head, face and neck

Abnormal movements that affect the head, face and neck are:

• essential/familial tremor

• tardive dyskinesia

• Tourette syndrome

• oculogyric crisis.

Two uncommon causes of abnormal movements of the face and head, hemifacial spasm and spasmodic torticollis; the latter has been discussed in the section ‘Neck pain’ in Chapter 11, ‘Common neck, arm and upper back problems’.

HEAD TREMOR

Head tremor is usually a manifestation of benign essential/familial tremor or cerebellar disease; it is very rare in Parkinson’s disease [31]. Essential/familial tremor may also affect the mouth and at times the voice. Benign essential/familial tremor is discussed in more detail in the section on abnormal movements of the upper limbs where this form of tremor is more common.

TARDIVE DYSKINESIA

Tardive dyskinesia is a neurological syndrome first recognised in the 1950s [32] that consists of repetitive, involuntary, purposeless movements affecting the mouth, lips and tongue with tongue protrusion; lip smacking, puckering and pursing; facial grimacing and rapid eye blinking. The involuntary movements occur during most of the waking hours. Typically it relates to side effects from certain drugs with an increased incidence in the elderly, although it may occur in the absence of any drug therapy, particularly in elderly edentulous patients. Tardive dyskinesia may also affect the limbs and trunk where the abnormal movements are more athetoid (repetitive involuntary, slow, sinuous, writhing movements) in nature.

MANAGEMENT of TARDIVE DYSKINESIA

This is one of the extrapyramidal syndrome side effects of central dopamine-blocking drugs such as the antipsychotics. It also occurs as a side effect of drugs used to treat Parkinson’s disease and some of the antiemetics such as prochlorperazine. The higher the dose and the longer the duration of treatment, the more likely is this condition to develop. It is less common with the new generation antipsychotic drugs [33]. Sometimes withdrawing the drug may lead to a resolution of the problem, particularly if the condition is identified very early, although improvement may take some time and the condition may persist for years after withdrawal of the offending drug. Tetrabenazine [34] and deep brain stimulation have been reported to be of benefit [35].

The other extrapyramidal side effects that can occur with the antipsychotic and antidepressant drugs include akathisia (unpleasant sensations of ‘inner’ restlessness that manifests itself as an inability to sit still or remain motionless), the neuroleptic malignant syndrome [36] and the serotonin syndrome. These entities are discussed below in the section, ‘Rare but life-threatening movement disorders’.

TOURETTE SYNDROME

Tourette syndrome is a condition predominantly seen in school-aged children [37]. The syndrome consists of tics that are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics), such as blinking, nose twitching, head and limb jerking, mouth opening, torticollis, shoulder rotation and sustained eye closure (blepharospasm). More complex motor tics may occur, such as making obscene gestures (copropraxia) and imitating others’ gestures (echopraxia). Burping, retching, vomiting, fist shaking, trunk bending, jumping or kicking are also seen. Phonic or vocal tics can also occur and these may include simply sniffing, grunting, coughing, clearing the throat, barking, screaming, shouting obscenities (coprolalia) and repeating one’s own utterances (echolalia). One of the diagnostic characteristics is the ability of the patient to suppress their tics. The motor and phonic tics may persist during sleep. It is much more common in males and is often associated with attention-deficit/hyperactivity disorder or obsessive–compulsive disorder.

MANAGEMENT of TOURETTE SYNDROME

The Tourette Syndrome Classification Study Group has created diagnostic criteria [38]. The aetiology is uncertain and treatment consists of behaviour therapy, particularly informing people who come into contact with the patient. Alpha-2 adrenergic agonists (clonidine) or dopamine receptor-blocking drugs (neuroleptics such as haloperidol and pimozide) are used to control the motor tics [37]. In severe and disabling motor tics, botulinum toxin (Botox) or deep brain stimulation may useful. Vocal cord injections can help phonic tics.

OCULOGYRIC CRISIS

This refers to the sudden involuntary contractions of some of the eye muscles that result in repetitive, conjugate ocular deviations usually, although not always, in an upward direction. The attack or crisis may last from seconds to minutes. Oculogyric crisis is most commonly seen following exposure to neuroleptic drugs. The incidence of oculogyric crises in patients treated with chronic neuroleptic therapy may be as high as 10%.

AETIOLOGY and MANAGEMENT of OCULOGYRIC CRISIS

Tetrabenazine, gabapentin, domperidone, carbamazepine and lithium carbonate have all been reported to trigger oculogyric crises. Oculogyric crisis may occur in patients with dopa-responsive dystonia, bilateral paramedian thalamic infarction, herpes encephalitis, cystic glioma of the posterior 3rd ventricle and Wilson’s disease.

The acute oculogyric crises can be terminated with an injection of intravenous anticholinergics or diphenhydramine. Diphenhydramine, 25 or 50 mg IV, is probably the treatment of choice for this condition. Oral clonazepam may be effective for patients with chronic neuroleptic-induced oculogyric crises that are resistant to anticholinergics [39].

HEMIFACIAL SPASM

Hemifacial spasm consists of brief clonic movements of the facial muscles on one side. Involvement of the orbicularis oculi results in repetitive blinking whereas involvement of the orbicularis oris causes repetitive twitching of the side of the mouth. It is believed to be due to a blood vessel irritating the proximal facial nerve near where it emerges from the brainstem.

Abnormal movements of the limbs

There are a large number of abnormal movements in the limbs. The more common seen in clinical practice are:

• benign essential or familial tremor

• the tremor of Parkinson’s disease

• cerebellar or intention tremor

• myoclonus

• hemiballismus

• chorea and athetosis

• orthostatic tremor

• paroxysmal kinesogenic choreoathetosis.

Some abnormal movements occur only with activity, others occur at rest and the patient is unable to keep still (see Figure 13.5). Most are abolished by sleep, but myoclonus and hemiballismus can occur while the patient is asleep.

FIGURE 13.5 The more common abnormal movements that occur in the limbs

ABNORMAL MOVEMENTS WHERE THE PATIENT CANNOT KEEP STILL

Parkinson’s disease: Parkinson’s disease was first described by James Parkinson in 1817 [40]. Resting tremor abolished by movement is often the initial symptom although occasional patients with Parkinson’s disease may have a non-resting tremor. The associated features of rigidity and bradykinesia that are characteristic of Parkinson’s may be minimal or absent in the very early stages. Patients do not complain that their limbs are rigid or stiff; they tend to say that the muscles in the arms and legs ache and they do not work as well. With advanced disease there is increasing inability to undertake activities of daily living that results from the bradykinesia, although patients often assume it is simply the ageing process! Patients with Parkinson’s disease walk with a slightly stooped posture and do not swing their arms when they are walking.

AETIOLOGY and MANAGEMENT of PARKINSON’S DISEASE

The aetiology of Parkinson’s disease is unknown, although in some patients there is a genetic predisposition and mutations in the parkin gene are linked to autosomal recessive juvenile parkinsonism [41].

At the time of writing there is no effective treatment to arrest the progression of the disease. Management is largely directed towards alleviation of the symptoms of Parkinson’s while trying to minimise the short- and long-term side effects of the drugs. In essence, the initial response to levodopa is very gratifying, and the first few years of treatment consist of gradually increasing drug therapy as the condition becomes more severe. This is replaced in later years by the progressive reduction in the doses of drugs to manage the side effects.

When reviewing patients with Parkinson’s disease, it is important to clarify the exact time of day that they take each of their medications and how long the benefit persists after taking the individual dose. This will help differentiate between the motor fluctuations that represent end-of-dose failure (the beneficial effect of the drug wearing off after a period of time) and the motor fluctuations referred to as the ‘on–off phenomena’ that can be likened to someone pushing a button on and pushing a button off, where the patient develops increasingly severe symptoms of Parkinson’s unrelated to the timing of medication. The former may respond to more frequent doses of levodopa and drugs that prolong the duration of benefit of levodopa; the latter is very difficult to treat but may respond to dopamine agonists.

Although levodopa is the recognised ‘gold standard’ drug for the symptomatic relief of Parkinson’s disease, the efficacy diminishes after 4–5 years and is supplanted by significant motor fluctuations [42]. Initially the duration of benefit from a single dose may last several hours; after many years the duration of benefit is significantly shorter. The combination of pramipexole and levodopa is superior to levodopa alone [43]. Stereotactic surgery and deep brain stimulation are other treatment modalities in drug-resistant cases. Patients have significant depression, dementia, psychosis and psychosocial issues that need considerable attention in addition to control of the tremor and the other motor manifestations of Parkinson’s disease [44].

Myoclonus: Myoclonus refers to sudden, shock-like, involuntary movements that can manifest in various patterns:

• focal, where a few adjacent muscles are involved

• multifocal, where many muscles jerk asynchronously

• generalised, where most of the muscles of the body are involved.

Myoclonic movements may be spontaneous or they may be activated by movement. Myoclonus is most commonly related to epilepsy and this has been discussed in Chapter 8, ‘Seizures and epilepsy’. Myoclonus might also occur after hypoxic brain damage either acutely, within 24 hours and while the patient is still comatose, or as a late complication. The myoclonus related to hypoxia is usually movement-induced, but it can be triggered by noise, touching the patient or tracheal suctioning. The acute form is associated with a poor prognosis. The chronic form develops days or weeks after the hypoxic insult and predominantly consists of an action myoclonus affecting the limbs. Violent flexion movements of the body, head and neck are precipitated by movement.

Propriospinal myoclonus (PSM) is a rare movement disorder characterised by myoclonic jerks arising in muscles corresponding to a single myotome and spreading rostrally and caudally to the other myotomes. PSM can be idiopathic, related to spinal cord lesions, drug use, malignancy or infection [45]. Patients present with myoclonic jerks involving abdominal wall muscles which worsen when lying down.

MANAGEMENT OF MYOCLONUS

MRI with diffusion tensor imaging detects abnormalities in patients with PSM [45]. Clonazepam, piracetam and valproic acid are the first-line treatments for post-hypoxic action myoclonus or PSM. Propofol and midazolam may be needed in the acute hypoxic form [46]. Zonisamide has been recommended for PSM [45].

Chorea and athetosis: Chorea is the ceaseless irregular, rapid, uncontrolled complex body movements that look well coordinated and purposeful but are in fact involuntary. The term ‘chorea’ is derived from the Greek word ‘choreia’ or ‘khoreia’ for dancing. Chorea was thought to be suggestive of a grotesque dance. Chorea can affect the face, arms or legs. The abnormal movements are almost continuous.

Athetosis consists of repetitive involuntary, slow, sinuous, writhing movements, especially severe in the hands.

Choreoathetosis is a movement of intermediate speed, between the quick, flitting movements of chorea and the slower, writhing movements of athetosis.

Chorea is very uncommon; Huntington’s disease is now the main cause with Sydenham’s chorea largely disappearing along with rheumatic fever. A very rare but treatable cause of chorea is Wilson’s disease [47]. There are a number of even rarer inherited movement disorders that could result in dystonia, chorea or ataxia [48, 49, but are beyond the scope of this book.

HUNTINGTON’S DISEASE: Huntington’s disease [50] is a hereditary disorder with the genetic defect on the short arm of chromosome 4. The genetic defect leads to altered function of the ubiquitous protein, huntingtin, that culminates in neuronal loss in the caudate nucleus. The number of tri-nucleotide repeats (cysteine-adenine-guanidine; CAG) influences whether the disease shows incomplete or complete penetrance and also influences the age of onset, with juvenile-onset Huntington’s patients typically having more than 55 tri-nucleotide repeats.

Huntington’s disease is characterised by the insidious onset in middle age (35–44 years of age) of progressive cognitive decline associated with abnormal movements and psychiatric disturbances. The chorea may not be present at onset; often the initial symptoms are unsteadiness and a lack of coordination with the cognitive decline and psychiatric disturbances appearing later. Chorea is the typical movement disorder but often rigidity, bradykinesia and dystonia may predominate and be more disabling. Rarely does it develop before the age of 20 where it is referred to as juvenile Huntington’s disease. In juvenile Huntington’s disease, the symptoms are quite different – the patient often presents rigid and akinetic (absence or poverty of movement) – and the progression to disability is more rapid. The inheritance pattern of Huntington’s disease is autosomal dominant.

SYDENHAM’S CHOREA: Sydenham’s chorea was first described in 1686 by Thomas Sydenham in a work entitled ‘Schedula monitoria de novae febris ingress’, but it was not until 180 years later (in 1866) that the association with rheumatic fever was appreciated by Roger. It is a complication of rheumatic fever following infection with particular strains of streptococci (i.e. group A beta-hemolytic streptococci). It predominantly affects children although it can be seen in adults. It is much rarer these days since the virtual abolition of rheumatic fever.

The antecedent sore throat, polyarthritis and subcutaneous nodules the size of peas at joints such as the elbows and knees, together with the characteristic pink-red macular rash referred to as erythema marginatum, are the clues to the diagnosis. Sydenham’s chorea is a self-limiting illness that initially worsens over 2–4 weeks and then subsequently resolves spontaneously over 3–6 months, although some patients may have waxing and waning symptoms for up to 12 months [51].

WILSON’S DISEASE: Wilson’s disease is an autosomal recessive disease caused by mutations in the ATP7B gene. The mutated gene prevents the transport protein from functioning properly, allowing copper to accumulate in the liver, brain, kidneys and skeletal system [47].

The neurological manifestations are the most common presentation; patients with liver disease present with jaundice. Although chorea occurs in Wilson’s disease, it is not the commonest manifestation; the majority present with features of parkinsonism, dystonia, ataxia, pyramidal signs, seizures, myoclonus and athetosis.

MANAGEMENT OF WILSON’S DISEASE

The diagnosis of Wilson’s disease is established by the presence of Kayser–Fleischer rings on the cornea, decreased serum ceruloplasmin, elevated 24-hour urine copper or increased hepatic copper content. Unfortunately, none of these findings is entirely sensitive or specific [48]. Characteristic MRI abnormalities in patients with Wilson’s disease consist of axial T₂WI bilateral basal ganglionic and thalamic hyperintensity in addition to mild to moderate diffuse atrophy [47]

Treatment is usually with drugs that reduce copper absorption (zinc acetate or zinc sulfate) or chelating agents such as penicillamine. Liver transplantation is an option in patients who fail to respond or cannot tolerate medical therapy [52]

Symptomatic treatment for chorea can be achieved with dopamine-depleting agents such as tetrabenazine or reserpine, benzodiazepines such as clonazepam or diazepam and dopamine antagonists such as the neuroleptic drug haloperidol.

ABNORMAL MOVEMENTS THAT OCCUR WITH ACTIVITY

Benign essential or familial tremor: Essential and familial essential tremor [53, 54] are the most common movement disorders in the elderly and the most common cause of an action tremor [55]. It can occur in patients in their teens.

Typically, the benign essential/familial tremor occurs when patients are either moving their arms or holding an object such as a book or a cup of tea where the cup rattles in the saucer and patients have to resort to half-filling their cup in order not to spill the tea. Eating becomes more difficult as the patient repeatedly spills food off the fork or soup out of the spoon. Although the tremor is bilateral, one side may be more severely affected than the other. The tremor sometimes leads to physical disability but progression to disability is usually very slow. Many patients are socially disabled as they are ‘too embarrassed’ to go out. Familial tremor is usually inherited as an autosomal dominant trait but with variable penetrance. Apart from the tremor, neurological examination is otherwise normal, in particular there is no rigidity or bradykinesia.

Differentiating Parkinson’s from essential/familial tremor: Table 13.2 shows the differences between the tremor of Parkinson’s and that of familial essential tremor.

TABLE 13.2

The different features of the tremor of Parkinson’s disease and essential/familial tremor

Clinical feature	Parkinson’s	Essential/familial
Affects the head and voice	No	Yes
Present at rest	Yes	No
Present when holding objects	No	Yes
Worse with walking	Yes	No
Influenced by alcohol	No	Yes
Frequency	3–6 Hz	5–12 Hz
Family history	Occasional	Often (familial)

INVESTIGATION and TREATMENT of ESSENTIAL TREMOR

It is important to exclude hyperthyroidism in patients with ‘essential tremor’. Genetic susceptibility loci have been identified in the FET1 (also known as ETM1) gene located on chromosome 3q1 [56] and ETM mapped to chromosome 2p22–25 [57].

There is no cure and many patients simply require reassurance about the benign nature of the tremor. Small doses of alcohol can be used to reduce the severity of mild tremor. In patients with more severe tremor, low-dose primidone (commencing with ¼ of a tablet or 62.5 mg and increasing to the minimum required or maximally tolerated dose, as much as 250 mg/day) or moderate dose propranolol (commencing with 10 mg and increasing slowly up to 120 mg/day) has been shown to reduce the severity of the tremor [58]. Osteoporosis commonly coexists in the elderly and primidone can exacerbate osteoporosis. Other medications include alprazolam, gabapentin, topiramate, nimodipine, clozapine and clonidine. In patients who are resistant to pharmacological therapy, either thalamotomy or deep brain stimulation may be of benefit [58].

Cerebellar or intention tremor: Cerebellar tremor is also referred to as intention tremor. These patients present with tremor when using their arms. There is no tremor at rest, little or no tremor with the hands outstretched but obvious tremor when the patient is asked to perform finger-to-nose or heel-to-shin testing where instability is noticed as the patient stretches to reach the distant target. The oscillations of intention tremor are perpendicular to the direction of movement and usually of low frequency, less than 5 Hz.

Intention tremor occurs in patients with MS, Friedreich’s ataxia, cerebellar infarction and degeneration.

TREATMENT for INTENTION TREMOR

There is no specific treatment for intention tremor; drugs such as clonazepam, carbamazepine, odansetron, isoniazid and physostigmine have all been tried with variable success [59]. In refractory cases, brain stimulation may be of benefit [60, 61].

ORTHOSTATIC TREMOR: Orthostatic tremor is a condition where the patient finds it impossible to stand still for any length of time without developing an increasingly severe sensation of instability (not dizziness) with their body developing a tremulous sensation. Patients rarely fall and usually hang on to something, sit or commence walking. Many patients avoid stopping while walking in order to avoid this sensation. The neurological examination is otherwise normal. Most cases are idiopathic [62], but it has been described in progressive supranuclear palsy [63] and following head injury [64].

TREATMENT of ORTHOSTATIC TREMOR

Clonazepam and primidone, particularly a combination of both drugs [65], and pramipexole [66] have been reported to reduce the severity of orthostatic tremor although none has been subjected to randomised controlled trials. Benefit from deep brain stimulation has also been described [67].

Action myoclonus: Myoclonus is the one abnormal movement that occurs at rest and also persists in sleep. Action myoclonus refers to sudden arrhythmic muscular jerking induced by voluntary movement. The condition is usually associated with diffuse neuronal disease, such as post-hypoxic encephalopathy [68], uraemia and various forms of progressive myoclonic epilepsy such as the Ramsay–Hunt syndrome [69].

Paroxysmal kinesogenic choreoathetosis: Paroxysmal kinesogenic choreoathetosis (PKC) has its onset in childhood or early adulthood. The characteristic feature is discrete episodes of abnormal movements precipitated by sudden movement such as standing up from sitting or being startled. Chorea occurs as does hyperkinesias, dystonia, athetosis and ballism. The neurological exam is normal between the events. The attacks are brief (< 5 minutes) and may occur several times a day.

MANAGEMENT of PAROXYSMAL KINESOGENIC CHOREOATHETOSIS

Linkage has been established in eight Japanese families to chromosome 16p11.2-q12.1 [70]. The condition responds very well to low-dose anticonvulsant therapy such as carbamazepine or phenytoin [71].

ABNORMAL MOVEMENTS THAT OCCUR DURING SLEEP

Myoclonus has already been discussed; the other abnormal movement that occurs during sleep is hemiballismus.

Hemiballismus: Hemiballismus (derived from the Greek word ‘ballismos’ that means jumping about or dancing) is considered a rare form of chorea and is almost continuous, violent, coordinated involuntary motor restlessness of half (very rarely bilateral, referred to as paraballism) of the body. The movements are usually continuous contorting movements and often rotatory in nature. It is most marked in the upper extremities and usually caused by a lesion involving the subthalamic nucleus of the opposite side of the brain, but it can arise from contralateral lesions in the cortex, basal ganglia and thalamus [72]. The commonest cause is an infarct, but it has been reported with demyelinating disease.

Although spontaneous remission is common, hemiballismus is a potentially life-threatening disorder and therapy is essential.

MANAGEMENT of HEMIBALLISMUS

An MRI scan, in particular a diffusion-weighted MRI scan, may define the site of the pathology in patients with hemiballismus. Pharmacological agents include haloperidol, risperadone, clonazepam and baclofen. Pallidotomy or thalamotomy may be necessary in intractable cases.

Rare but life-threatening movement disorders

These have also been referred to as movement disorder emergencies and are defined as any movement disorder that evolves over hours to days and include acute parkinsonism, dystonia, chorea, tics and myoclonus. The commonest is drug-induced (neuroleptics and antiemetics) parkinsonism, and cyanide, methanol, carbon monoxide, carbon disulfide, organophosphate pesticides and the designer drug MPTP are some of the toxins that may produce a severe encephalopathy with clinical features of parkinsonism. Only neuroleptic malignant syndrome and serotonin syndrome will be discussed here. For an excellent review of movement disorder emergencies see the review by Poston [39].

NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic malignant syndrome is a very rare potentially life-threatening but treatable idiosyncratic response to D₂-dopamine receptor agonists such as antiemetics, droperidol, anaesthetic agents and antipsychotic drugs. A rapid increase in the dose may increase the risk of neuroleptic malignant syndrome. It can also occur if treatment for Parkinson’s is suddenly withdrawn.

The clinical features consist of rigidity, fever, sweating, severe hypertension and altered conscious state. Creatinine kinase is elevated and liver function abnormalities occur. Dehydration leads to renal impairment. Features of parkinsonism and the presence of fever should alert the clinician to the possibility of this condition. It can occur at any age and in either sex.

TREATMENT of NEUROLEPTIC MALIGNANT SYNDROME

Dopamine agonists, levodopa, lisuride and dantrolene are the pharmacological agents used to treat neuroleptic malignant syndrome.

SEROTONIN SYNDROME

Serotonin syndrome [73] is caused mainly by the serotonin-specific reuptake inhibitors (sertraline, fluoxetine, paroxetine and fluvoxamine), clomipramine, ecstasy and the combination of monoamine oxidase inhibitors and meperidine that result in an increase in the biological activity of serotonin.

Serotonin syndrome consists of fever with confusion, hypomania, agitation, tachycardia, fever, sweating, shivering, tremor, diarrhoea, hypertension, incoordination, myoclonus, rigidity and hyperreflexia. The clinical features of serotonin syndrome and neuroleptic malignant syndrome overlap; it is the presence of myoclonus that distinguishes serotonin syndrome from neuroleptic malignant syndrome.

TREATMENT of SEROTONIN SYNDROME

Propranolol, chlorpromazine, diazepam, methysergide and, in particular, cyproheptadine are recommended for the treatment of serotonin syndrome [74, 75].