Introduction

Peripheral neuropathy (PN) represents nerve damage outside the central nervous system. It includes lower motor neurone (LMN) damage as well as sensory neuropathies. Radiculopathy (nerve root damage) is also part of PN.

Ability to differentiate between upper motor neurone (UMN) and LMN damage is fundamental to understanding PN (see Table 11.1). Cranial nerves represent a special type of peripheral nerve emanating from the brainstem. This raises an ‘old chestnut’, namely facial weakness of either UMN or LMN origin.

TABLE 11.1 Differentiation between upper motor neurone and lower motor neurone damage

All too often patients are diagnosed with ‘UMN facial palsy’ and by definition ‘palsy’ is of LMN origin (as is the case with bulbar palsy and pseudo-bulbar palsy, the latter being of UMN origin and hence not really a palsy—thus the use of the term ‘pseudo’). It follows that ‘UMN facial palsy’ is stating ‘UMN LMN weakness’ which is inappropriate. The word ‘palsy’ is a corruption of the French word ‘paralysie’, meaning paralysis but usually implying LMN lesion.

A LMN facial nerve lesion (cranial nerve VII palsy) affects both upper face (forehead) and lower face—hence the saying ‘lower is upper’, while an UMN facial weakness affects only the lower part of the face justifying the statement ‘upper is lower’. To be correct one should refer to either facial palsy, implying LMN deficit, or UMN facial weakness, implying involvement of only lower face.

There are some conditions that may affect both UMN and LMN,¹ such as motor neurone disease (often referred to as amyotrophic lateral sclerosis) or subacute combined degeneration, as may occur with vitamin B₁₂ deficiency.²

What follows in this chapter is a discussion of the nature of nerve damage, causes of PN, diagnosis thereof, a look at some focal neuropathies, nutritionally induced neuropathies and some illnesses associated with PN. The aim is to help general practitioners become more involved in patient care and, hence, better enjoy the therapeutic partnerships with the consultant.

The Nature of Nerve Damage

Nerves transmit their messages via an electrical impulse from the nerve cell (the cell of the neurone) down the length of the ‘arm’ of the cell (the axon) to pass the message either to another nerve or the end target organ. The message is sent via the impulse causing release of the neurotransmitters that produce the desired effect, be it to stimulate or suppress a subsequent response, such as causing a muscle to contract or to stimulate another nerve (see Fig 11.1).

FIGURE 11.1 Schematic of neural transmission.

To speed up transmission the axons of the nerves are usually coated with myelin, which acts in a similar fashion to the plastic coating that insulates and allows unimpeded passage of electrical current down an electrical wire (see Fig 11.1). Along the myelinated nerve fibre the impulse ‘jumps’ between Nodes of Ranvier, breaks in the myelin.

In the same way the wire within the plastic transmits the electrical current, so too does the axon send the neuronal impulse. It follows that damage to the axon (analogous to the electrical wire) will reduce the amount of message able to be transmitted. In neurophysiological terms, axonal damage will reduce the amplitude of the impulse and hence the amplitude of the action potential generated,³ namely the size and strength of the message received rather than the speed of the transmission.

Transmission speed (or conduction time) is facilitated by the myelin sheath. It follows that damage to myelin, as occurs in demyelinating illnesses (such as Landry-Guillain-Barré syndrome, often referred to as GBS—omitting the name Landry, or multifocal motor neuropathy) will slow conduction time.⁴ In the same way damage to the plastic coating of the electrical wire will ultimately allow the wire to corrode and be damaged, so too will established demyelination allow subsequent axonal damage.⁵

From the above it can be seen that nerve damage will occur if there is a disease process that will remove myelin from nerves (demyelination causing slowing of conduction); axonal damage causing less impulse to be transmitted; or a combination of both. Understanding of this will enhance appreciation of the results from neurophysiological testing.

When nerves are damaged it may be akin to a short circuit, to continue the electrical wire analogy. Thus nerves may ‘fire’ spontaneously. This may result in the activation of a single muscle fibre (called fibrillation, see Fig 11.2) or a group of muscle fibres known as a motor unit, which is limited to muscle fibres innervation by a single motor nerve (called fasciculation, see Fig 11.3).

FIGURE 11.2 Fibrillation.

FIGURE 11.3 Fasciculation.

Both fibrillations and fasciculations are recorded using needle electromyography to record spontaneous firing. Fibrillations are not generally visible with the exception of the tongue, which may be wasted and show fibrillations in motor neurone disease. Fasciculations can be seen as small muscle twitches as they involve more than a single muscle fibre. Fasciculations may be completely benign as can occur in marathon runners, or may reflect significant PN and often accompany motor neurone disease.

Causes of Nerve Damage

PN can be the result of either local damage or a more generalised process affecting a wider target (see Box 11.1).

The most common cause of local damage is consequent to pressure, which causes a ‘neurapraxia’ that damages the nerve at the site of the pressure. An example of this process is damage to the lateral popliteal nerve with resultant foot drop. The lateral popliteal nerve activates the tibialis anterior muscle that dorsiflexes the foot.⁶ Similarly, direct damage to the radial nerve as it transverses the humeral groove in the humerus bone will result in wrist drop due to deficits of wrist extension.⁷

Perhaps the best-known local nerve damage is carpal tunnel syndrome (CTS), which affects the median nerve. This causes weakness of the muscles innervated by the nerve plus specific sensory deficit referable to local median nerve damage (see Fig 11.4).

FIGURE 11.4 Sensory innervation of hand.

Only four intrinsic hand muscles are innervated by the median nerve.⁸ The remainder are innervated by the ulnar nerve. There is a mnemonic to remember these four muscles: LOAF (Lateral two lumbricals, Opponens pollicis, Abductor pollicis brevis and Flexor pollicis brevis).

Generalised PN results from a systemic problem that can be the result of a variety of toxins, for example drugs (e.g. vincristine)⁹ or infections, which may be the precipitant for conditions such as motor neuropathy (as may occur with infectious hepatitis)¹⁰. A variety of other environmental toxins, such as lead and other heavy metals,¹¹ can also cause pure motor neuropathy.

Conditions such as Landry-Guillain-Barré syndrome (GBS, also known as idiopathic ascending inflammatory polyradiculopathy)¹² and chronic inflammatory demyelinating neuropathy¹³ (CIDP) represent allergic responses to reputed infective agents causing demyelinating radiculopathy or neuropathy.^12,13

Diagnosis of Nerve Damage

Focal Neuropathies

The most common focal PN is CTS,⁸ which reflects damage to the median nerve due to entrapment at the level of the carpal tunnel at the wrist. There should be an appropriate history (with dysaesthesia of the hand causing waking from sleep that often responds to shaking to return sensation). There should also be weakness of the median nerve innervated muscles (remember the mnemonic LOAF, as above), especially with weakness of abductor pollicis brevis and lateral two lumbricals (see Figs 11.5 and 11.6). There may be a sensory deficit (see Fig 11.4), which may not be as anatomically distinct as shown but, as a minimum, sensation in the thenar eminence should be less than that over the hypothenar eminence.

FIGURE 11.5 Testing power in abductor policis brevis.

FIGURE 11.6 Testing lateral two lumbricals.

Causes of CTS include: using vibrating equipment, such as jack hammers; repeated pressure from using tools, such as a screwdriver with the palm pushing down on it; but most commonly from sleeping in such a position as to cause marked palmar flexion of the wrist thereby impeding the blood supply to the nerve. Before contemplating either neurophysiology or surgical referral, the most common effective treatment is to organise a physiotherapist to provide a moulded night splint made specifically to meet the anatomy of the patient (see Fig 11.7).

FIGURE 11.7 Night splint to immobilise at night—to treat carpal tunnel syndrome.

The next most common PN is an ulnar neuropathy¹⁴ at the elbow. This causes dysaesthesia along the ulnar border of the forearm, little finger (D5) and medial half of the ring finger (D4) (see Fig 11.4). It causes weakness of the ulnar-innervated muscles of the hand, typified by abductor digiti minimi that forces the little finger away from the rest of the fingers and away from the palm (see Fig 11.8). It also causes weakness of the medial two lumbricals (see Fig 11.9). Long-standing ulnar neuropathy may cause wasting of the first dorsal interosseus muscle best seen in the dorsum of the hand, the muscle between the thumb and index finger (D1 and D2).

FIGURE 11.8 Testing power in abductor digiti minimi.

FIGURE 11.9 Testing power in medical two lumbricals.

The main cause of ulnar neuropathy is direct trauma to the nerve as might occur when turning over in bed at night. This results in the whole body’s weight being supported by the elbow and hence the ulnar nerve as it crosses the elbow at the ulnar groove next to the humeral epicondyle. The way to treat this is to pad the elbow over the region. This includes the medial humeral epicondyle and olecranon of the ulnar bone. The easiest way to do this is to get a piece of foam rubber, approximately 2 cm thick and about 5–10 cm in diameter. This is placed in position and held either with a bandage or more simply using a large sports sock with the toe cut out so that it can be slipped up the forearm and over the elbow (see Fig 11.10). Such padding prevents repeated pressure upon the nerve that causes nerve damage (neuropraxia) by squashing the nerve against the hard bony surfaces while rolling over. The splint only needs to be worn at night while sleeping.

FIGURE 11.10 Padding elbow to protect ulnar nerve.

Should this simple intervention fail to relieve symptoms then it is time to refer the patient for specialist opinion and to order electrophysiology.

Nutritionally Induced Neuropathies

Various vitamin deficiencies are known to cause PN, such as B-group vitamins, possibly in association with alcohol abuse.¹⁵ The general practitioner should prescribe thiamine (B₁) to all patients with suspected alcohol dependence. A proper history, including a dietary history, should be an integral part of the diagnostic process.

The onset of PN can be slow and subtle but damage can be profound, as in the case with B₁₂ deficiency that can cause CNS and PN damage.¹⁶ Parenteral B₁₂ injections may both arrest and allow some restorative benefits. Measurement of B₁₂ and folate must be part of the patient assessment when considering PN. Folic acid is an essential component of B₁₂ metabolism, but is often overlooked. Replacement with 5 mg folate per day is simple and effective.

Other nutritional conditions include pellagra,¹⁷ with its triad of gastrointestinal symptoms, dementia and PN. It is caused by nicotinic acid (niacin) deficiency. Some drugs, such as penicillamine or isoniazid, may cause B₆ (pyridoxine) deficiency. B₁₂ and B₆ deficiency may cause elevation of homocysteine, which is implicated in stroke evolution due to hyperviscosity. Nutritional deficiencies may reflect malabsorption rather than poor dietary intake. Without a high index of suspicion, such causes may be overlooked.

Illness Associated with Peripheral Neuropathies

The most common diagnosis associated with diffuse PN is diabetes. This should be a fundamental consideration when diagnosing PN.¹⁸ Blood sugar level and glycosylated haemoglobin (HbA_1c) should be ordered early in the evaluative process. Where there are haemoglobinopathies, such as thalassemia, fructosamine measurement may be preferable to HbA_1c. Initial control of diet may be all that is required, but it has been personal preference to involve an endocrinologist early in the therapeutic process regarding diabetes and to advocate early introduction of insulin once PN has been confirmed. The variety of neuropathic complications with diabetes (such as painful diabetic amyotrophy) may necessitate a wider team approach and even use of immuno-modulating agents, such as IV immunoglobulin, but this is outside the scope of this review.

Any condition that may adversely affect the nerve’s blood supply, as with the blocking of the vasa nervorum in diabetes, has the potential to cause PN. It follows that any cause of vasculitis (such as polyarteritis nodosa or lupus erythematosus) may cause PN, particularly mononeuritis multiplex, which may affect specific nerves rather than cause a generalised PN. Antinuclear antibody (ANA) and extractable nuclear antibody (ENA) should be included in the diagnostic process. In addition, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should be measured in suspected cases of PN. Treatment of these vasculitites by the specialist working with the general practitioner will not be further discussed.

Sarcoidosis is also a well-recognised cause of mononeuritis multiplex (including isolated nerve damage). Angiotensin converting enzyme (ACE) should be measured as part of the evaluation.

Neoplasia can cause PN via several routes, be it direct nerve damage (due to a space-occupying or pressure effect), as a consequence of cachexia or as a paraneoplastic expression, which can cause both small-fibre or large-fibre involvement. If in doubt, the general practitioner should look for a primary source using chest imaging and possibly chest and abdominal CT. Anti-neuronal antibody screening, such as anti-Hu together with other tumour markers—alpha-feta protein (AFP) or carcino-embryonic antigen (CEA)—may assist. Agents used to treat neoplasia (such as vincristine or thalidomide) may cause PN. Other medications may be associated with PN, such as statins—now used for more than just hyperlipidaemia—in stroke prevention for vessel-wall stabilisation and even for conditions such as dementia or multiple sclerosis.¹⁹

The cardiac medication amiodarone, the urinary antibiotic nitrofurantoin or the antiepileptic medication phenytoin (via its anti-folate effects) may all cause PN. Unless the general practitioner is vigilant, such iatrogenic causes may be overlooked. Medications may serve as a trigger to evoke conditions known to cause PN. One such condition is porphyria, with a pure motor neuropathy that may be provoked by use of barbiturates. Being a rare condition it is easily overlooked, but a detailed medication history may provoke its consideration.

Other illnesses to be kept in mind when considering PN include: hepatitis (particularly B and C); AIDS and HIV; mononucleosis with Epstein-Barr virus; herpes (both shingles and chicken pox); and even Lyme disease. An overview such as this cannot be exhaustive, but the general practitioner should have a list of treatable PNs to ensure patients benefit from intervention when it is available.

Inflammatory Neuropathies

Landry-Guillain-Barré syndrome (GBS) is a rapidly progressive and treatable cause of PN or ascending radiculopathy. While its treatment is the domain of the neurologist, its diagnosis and treatment are often delayed because it has not reached the radar screen of many general practitioners. It is easy to dismiss the early presentation of GBS. The answer is to suspect it in people with motor (and sometimes also sensory) symptoms, usually starting in the lower limbs and spreading rapidly. Initially there may be few signs, but a high index of suspicion will allow early access to IV immunoglobulin or plasmapheresis. High CSF protein, as found with lumbar puncture, is also a useful diagnostic clue with GBS.

Similarly, chronic inflammatory demyelinating polyneuropathy (CIDP) may be easily overlooked as a diagnostic entity, so the patient is denied appropriate and effective therapy. Only with a high index of suspicion, complemented by markedly slowed nerve-conduction electrophysiology, will the diagnosis be apparent and treatment with IV immunoglobulin commenced.

Other Considerations

One should not ignore the hereditary causes of PN, including inherited propensity to pressure palsies. Treatment is usually symptomatic. Heavy metals such as lead or mercury, or other toxins such as nitrous oxide can cause PN.

Multifocal motor neuropathy with conduction block or progressive muscular atrophy (part of the motor neurone disease complex) are generally neurologists’ diagnoses but the general practitioner is the first port of call. With a high index of suspicion, they can dramatically reduce the time from onset to diagnosis and treatment. It follows that the general practitioner must retain an overview of PN, although early involvement of a specialist improves the therapeutic approach.

Conclusion

Often general practitioners exclude themselves from the management of PN, but the above demonstrates what a valuable role they can play. As with all neurology, a good history is indispensable as is a clear understanding of what to look for and how to differentiate LMN from UMN lesions (see Table 11.1). The general practitioner may be the person who diagnoses the treatable PNs, having a high index of suspicion and having ordered the appropriate tests (see Box 11.1).

The most common PNs presenting to the general practitioner are CTS and ulnar neuropathy, both of which respond well to conservative treatment that might completely do away with the need for referral to a specialist (Figs 11.4–11.10). Only in those few cases that fail to respond would there be a need to seek neurophysiological diagnostic confirmation and consultant involvement. Where doubt exists as to whether the patient has CTS or ulnar neuropathy or a more widespread PN, early referral to a consultant is advisable.

Lifestyle issues, such as alcohol dependence, dietary failings (such as B₁, B₆, B₁₂ or folate) and compliance with treatment for conditions like diabetes or use of inappropriate medications, are all issues that may be adequately and properly addressed by the general practitioner. With prompt diagnosis and treatment, many of these problems may not even require the consultant to become involved. It is gratifying to refer patients with unusual or complex diagnoses, which were correctly diagnosed and/or treated in general practice, and were referred simply to ensure all necessary procedures had been completed, rather than admitting failure and abrogating authority to the consultant. PN is one such area where the general practitioner can achieve good outcomes in many patients without needing to seek outside assistance.