12th August 2024

Neuropathies

Terminology

Neuropathies affecting a single nerve are termed mononeuropathies and are generally secondary to trauma or compression. Specific deficits and causes are discussed below.

Mononeuritis multiplex involves multiple, asymmetric, non-contiguous nerves. It is most commonly caused by a vasculitic process (polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus, or the ANCA-associated vasculitides) but can also have infectious (HIV, hepatitis), drug-related or infiltrative (sarcoidosis) aetiologies.

Polyneuropathy refers to a generally systemic, relatively homogenous process affecting multiple peripheral nerves.  They can be divided by aetiology or by pathological process (axonal or demyelinating), as in the table below. Nerve conduction studies (NCS) can be used to differentiate these latter distinctions, with demyelination giving a slowed conduction velocity with or without conduction blocks. An axonal neuropathy, by contrast, decreases the amplitude of potentials (compound muscle action potentials, CMAPs, and sensory nerve action potentials, SNAPs) due to damage to axons, while conduction velocity is generally relatively preserved until the disease is severe.

Inherited neuropathies

Charcot-Marie-Tooth

CMT, also known as the hereditary motor sensory neuropathies (HMSN), refers to a group of disorders with inherited mutations to myelin (or rarely axonal) proteins.

• CMT1, the most common form, is characterised by distal lower limb sensory and motor loss, bony foot deformities (pes cavus, often with fractures followed by remodelling). Reflexes are typically diminished or absent. Biopsy may show characteristic ‘onion-bulb’ demyelination.
• CMT2 is a rare axonal form, characterised by sensory loss, distal weakness, atrophy, hyporeflexia and variable foot deformity. It presents in the teens to early twenties.

The mainstay of treatment is supportive, with orthotics and physiotherapy playing a large role.

Hereditary neuropathy with pressure palsies

HNPP describes a recurrent, transient, acute demyelinating mononeuropathy at sites of compression or trauma. Nerves commonly affected include radial, peroneal, median, axillary, ulnar, or brachial plexus.

Metabolic and toxic neuropathies

Diabetic neuropathy

This can manifest in multiple different ways, the most common of which is a length-dependent (i.e. distal onset ‘glove-and-stocking’), symmetric, sensory-predominant neuropathy. Other forms include autonomic neuropathy, polyradiculopathies, cranial mononeuropathies (typically oculomotor nerve), and mononeuritis multiplex.

Alcoholic neuropathy

This symmetric distal-onset neuropathy is due to direct axonal toxicity, often complicated by nutritional deficiency causing demyelination. Sensory symptoms generally precede motor. Dry beriberi is a term used to describe a demyelinating polyneuropathy caused by thiamine deficiency, which may occur in the context of chronic alcohol misuse.

Porphyria

Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder resulting from a deficiency of porphobilinogen deaminase. Most patients present in their 20-30s, and females are much more likely to manifest symptoms, though gene frequency is equal between males and females. Exacerbating factors include smoking, medications, stress and sex hormones.

The constellation of symptoms includes abdominal pain, vomiting, psychiatric symptoms, peripheral neuropathies (motor predominance), hypertension, tachycardia and hyponatraemia. Severe manifestations include seizures, quadriplegia and respiratory failure. In an acute attack, urine may turn deep red on exposure to light and is tested for elevated urinary porphobilinogen. Treatment is with haem arginate (hemin).

Porphyria cutanea tarda (PCT) is caused by reduced uroporphyrinogen decarboxylase activity. Presentation is generally with a photosensitive rash. In later stages of the disease, a liver impairment may be seen. Testing shows increased plasma and urine porphyrins.

Lead poisoning

This may cause a similar pattern of symptoms to porphyria. The blood lead level is used to guide whether chelation therapy with DMSA (dimercaptosuccinic acid) or EDTA (ethylenediaminetetraacetic acid) is indicated.

Drug-induced polyneuropathy

Many drugs may cause peripheral neuropathy. Some of the most strongly associated are listed here:

• Antimicrobials: fluoroquinolones, nitrofurantoin, metronidazole, isoniazid and dapsone
• Chemotherapy agents: vinca alkaloids, taxanes and platinum-based regimens
• TNF (tumor necrosis factor) or immune checkpoint inhibitors
• Phenytoin
• Amiodarone
• Colchicine

Inflammatory neuropathies

Guillain-Barré Syndrome (GBS)

GBS is an acute inflammatory polyneuropathy which causes an ascending, progressive, symmetric weakness with loss of deep tendon reflexes. Sensory involvement (commonly hand and feet paraesthesias) is generally mild. It develops acutely or subacutely with a nadir at a maximum of 4 weeks and often follows infection – C. jejuni, EBV, CMV, influenza, HIV, or COVID-19 have all been implicated. CSF is generally normal apart from elevated protein, and anti-GM1 antibodies may be found, particularly in cases associated with C. jejuni.

Treatment, as with the variants below, is with IVIG or plasma exchange. It has a 5% mortality rate and 15% are unable to walk unaided at 1 year.

Miller Fisher syndrome (MFS)

MFS is a variant of GBS with eye involvement (ophthalmoplegia), ataxia and areflexia. It is associated with GQ1b antibodies.

Acute motor axonal neuropathy (AMAN)

AMAN is an axonal variant of GBS with no sensory involvement and often more rapid progression. It is strongly associated with C.jejuni and with anti-ganglioside antibodies (GD1a, GM1).

Chronic inflammatory demyelinating polyneuropathy (CIDP)

CIDP has a similar presentation to GBS but is chronically progressive (over several months).

Multifocal motor neuropathy (MMN)

MMN, or multifocal motor neuropathy with conduction block, is characterised by asymmetric motor deficits in peripheral nerves occurring over months to years, typically affecting the hands or legs. Nerve conduction studies show conduction blocks, anti-GM1 antibodies are generally positive, and treatment is with IVIG.

Mononeuropathies

Carpal tunnel syndrome

Compression of the median nerve at the wrist causes thenar wasting, weakness of ‘LOAF’ muscles (lateral lumbricals, opponens pollicis, abductor pollicis brevis and flexor pollicis brevis), and sensory loss over the palm and lateral three and a half fingers.

Other median nerve injuries

Damage at the elbow gives similar symptoms to those of carpal tunnel syndrome, with the addition of weakness of forearm pronation and wrist flexion.

Damage to the anterior interosseous branch nerve causes weakness of forearm pronation and flexion of the thumb and index finger. It most commonly occurs in the context of forearm trauma or neuralgic amyotrophy (a brachial plexopathy characterised by severe pain and weakness in the distribution of the upper brachial plexus).

Ulnar nerve injury

This generally occurs due to elbow trauma at the medial condyle or in Guyon’s canal in the wrist. It causes weakness of wrist flexors, interossei, medial two lumbricals, and hypothenar wasting. There is sensory loss over the ulnar border of the palm and medial 1.5 fingers.

Radial nerve injury

This is most commonly caused by humeral fracture or compression of the radial nerve in the spiral groove. Signs include weakness of wrist and finger extension and sensory loss over the dorsum of the hand.

Common peroneal nerve injury

Causes of common peroneal nerve injury include fibula fractures, leg crossing or stretching and leg casts. Signs on examination include weak dorsiflexion and eversion of the ankle and sensory loss to the dorsum of the foot. Inversion is innervated by the tibial nerve so is not affected, which helps to differentiate this from an L5 radiculopathy.

Posterior tibial nerve injury

Generally, this is injured in the ankle (tarsal tunnel) due to fractures of the talus, calcaneus or medial malleolus or rheumatoid disease. Signs include weak intrinsic foot muscles (e.g. inability to stand on tiptoes) and sensory loss over the sole of the foot.

Sciatic nerve injury

Injury in the gluteal region can damage the sciatic nerve, and this generally occurs secondary to hip dislocation or fracture, or hip surgery. Other causes include pelvic masses and piriformis syndrome. It presents with weakness of the hamstrings and muscles below the knee, sensory loss to the lower leg sparing the medial calf and foot arch and loss of the ankle reflex (with preserved patellar reflex).

Mid-femoral region injury can occur with femoral fracture or ischaemia. Signs are similar to the above but generally without hamstring involvement.

Femoral nerve injury

This has similar causes to gluteal-region sciatic injury. Typical signs are quadriceps weakness, sensory loss over the anterior and medial thigh, medial shin and arch, and a diminished patellar reflex with normal ankle jerk.

Lateral femoral cutaneous nerve

Meralgia paresthetica is a pure sensory syndrome caused by compression of the lateral femoral cutaneous nerve, characterised by anterior and lateral thigh pain. Risk factors include obesity, tight fitting clothes or belts, hip injuries or repetitive motion of the hip.

Morton’s neuroma

This describes nerve thickening between the 3ʳᵈ and 4ᵗʰ metatarsophalangeal joints, which can cause a burning pain.

Neuralgic amyotrophy

Also known as Parsonage-Turner syndrome, neuralgic amyotrphy is an inflammatory brachial plexopathy characterised by severe pain with later development of patchy weakness in the distribution of the upper brachial plexus.

References

• Manji H. Oxford Handbook of Neurology. Oxford Medical Publications; 2020
• Lewis RA. Chronic inflammatory demyelinating polyneuropathy: Aetiology, clinical features, and diagnosis [Internet]. Shefner JM (Ed). UpToDate. 2020 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/chronic-inflammatory-demyelinating-polyneuropathy-etiology-clinical-features-and-diagnosis
• Chandrashekhar S. Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis [Internet]. Shefner JM (Ed), Rabinstein AA (Ed). UpToDate. 2022 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/guillain-barre-syndrome-in-adults-pathogenesis-clinical-features-and-diagnosis
• Kang PB. Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis [Internet]. Nordli DR (Ed), Firth HV (Ed), Shefner JM (Ed). UpToDate. 2022 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/charcot-marie-tooth-disease-genetics-clinical-features-and-diagnosis
• Kang PB. Charcot-Marie-Tooth disease: Management and prognosis [Internet]. Nordli DR (Ed), Firth HV (Ed), Shefner JM (Ed). UpToDate. 2022 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/charcot-marie-tooth-disease-management-and-prognosis