Peripheral Neuropathy — DCE Clinical Case

Long case

Patient scenario

Mr RW is a 62-year-old man referred to the neurology service for evaluation of a rapidly progressive neuropathy. He has a 15-year history of type 2 diabetes (currently on metformin, gliclazide, and empagliflozin), hypertension, and dyslipidaemia, and a 20 pack-year smoking history. [1]

For the last 3 years he has had progressive burning numbness in both feet, worse at night, ascending from the toes to the mid-shin. He has lost the ability to feel the floor, has stumbled several times, and noticed that small foot injuries heal without pain. Two weeks ago, he noticed a painless ulcer under the right first metatarsal head, which prompted the referral. He has had erectile dysfunction for 2 years and light-headedness on standing. [1]

Over the last 6 weeks, he has developed severe, deep, burning pain in the right leg and foot, with abrupt weakness — he cannot dorsiflex the right foot (foot drop) and trips frequently. One week later, he developed numbness and tingling in the right little and ring fingers (ulnar distribution). These deficits evolved over days rather than the years of his foot numbness. He has lost 5 kg in weight and reports drenching night sweats over the same period. [1]

His medications are metformin 1 g twice daily, gliclazide 80 mg daily, empagliflozin 10 mg daily, perindopril 5 mg daily, atorvastatin 40 mg daily, and aspirin 100 mg daily. He drinks 30 g of alcohol daily. His father had type 2 diabetes and died of a myocardial infarction at 70. [1]

Examination findings

General inspection reveals a thin man (BMI 23, down from 26 six months ago). There is distal muscle wasting in the lower limbs, particularly the intrinsic foot muscles and the peroneal muscles on the right. There is a 2 cm painless ulcer with a clean base under the right first metatarsal head, surrounded by callus. The right common peroneal nerve is palpable and tender at the fibular head. Both feet are warm with palpable but mildly reduced pulses. [1]

Cranial nerves are intact. Upper limb examination is normal except for a right ulnar distribution sensory loss to pinprick in the little finger and medial half of the ring finger, with mild weakness (MRC grade 4) of right finger abduction and adduction. Upper limb reflexes are 2+ and symmetrical. [1]

In the lower limbs, tone is normal. Power is 4/5 in ankle dorsiflexion bilaterally, but on the right there is profound foot drop (0 to 1/5 ankle dorsiflexion and toe extension) with preserved plantarflexion (4/5), consistent with a right peroneal nerve lesion. Knee flexion, hip movements, and ankle inversion are preserved. Reflexes are 2+ at the knees bilaterally, and the ankle reflexes are absent bilaterally even with Jendrassik reinforcement. Both plantars are flexor. [1]

Sensation reveals a stocking-distribution loss of pinprick, light touch, and temperature to the mid-shin bilaterally, with loss of vibration sense (128 Hz tuning fork) at both great toes and the ankles. Joint position sense is impaired at the great toes. In the right hand, there is loss of pinprick in the ulnar distribution. Coordination is impaired on heel-shin testing bilaterally (sensory ataxia). Gait demonstrates a high stepping component on the right (steppage gait from foot drop) and a broad-based sensory ataxic component. Romberg is positive. [1]

His HbA1c is 78 mmol per mol (9.3 per cent). Full blood count shows a mild normocytic anaemia (haemoglobin 112 g per L). Urea and electrolytes, liver function, and thyroid function are normal. Vitamin B12 is 220 pmol per L (borderline). Serum immunofixation shows a small IgM kappa paraprotein (3 g per L). C-reactive protein is 48 mg per L. [1]

Candidate's opening statement (SASPOP)

"Doctor, my patient is Mr RW, a 62-year-old man with type 2 diabetes. His problems are: a chronic distal symmetric polyneuropathy from poorly controlled diabetes — 3 years of burning foot numbness, stocking sensory loss to the mid-shin, absent ankle reflexes, impaired vibration and joint position sense, a positive Romberg, and a painless foot ulcer; a superimposed subacute mononeuritis multiplex — a 6-week history of painful, asymmetric, stepwise involvement of the right peroneal nerve (profound foot drop) and the right ulnar nerve, which is the signature of vasculitic neuropathy and is a neurological emergency; systemic symptoms of weight loss and night sweats with a raised CRP, suggesting an underlying systemic vasculitis or paraproteinaemic process; a small IgM kappa paraprotein that requires characterisation, including exclusion of cryoglobulinaemic vasculitis and hepatitis C; autonomic neuropathy with erectile dysfunction and orthostatic symptoms; poor glycaemic control with an HbA1c of 78 mmol per mol; a borderline B12 level on metformin; a 20 pack-year smoking history contributing to his peripheral arterial disease and amputation risk; and a painless foot ulcer requiring urgent podiatric and vascular management. My priorities are to confirm the vasculitic neuropathy with a sural nerve biopsy, initiate urgent immunosuppression to prevent further irreversible nerve infarction, manage the foot ulcer aggressively to prevent amputation, optimise glycaemic and cardiovascular risk factor control, and characterise the paraprotein." [1]

Problem list

1. Chronic diabetic distal symmetric polyneuropathy with sensory ataxia and a positive Romberg.
2. Painless diabetic foot ulcer (right first metatarsal) — risk of deep infection and amputation.
3. Subacute vasculitic mononeuritis multiplex (right peroneal and ulnar) — neurological emergency.
4. Small IgM kappa paraprotein — possible cryoglobulinaemic vasculitis, anti-MAG, or incidental MGUS.
5. Systemic symptoms (weight loss, night sweats, raised CRP) — possible systemic vasculitis or malignancy.
6. Autonomic neuropathy (erectile dysfunction, orthostatic symptoms).
7. Poor glycaemic control (HbA1c 78 mmol per mol).
8. Borderline B12 on metformin.
9. Peripheral arterial disease and smoking — amputation risk. [1]

Integrated management plan

Confirm the diagnosis. Nerve conduction studies to document the background axonal DSPN and the superimposed axonal mononeuropathies. A sural nerve biopsy (ideally combined with a peroneus brevis muscle biopsy) to confirm vasculitic neuropathy [3], because the result will change management. A vasculitic and paraproteinaemic blood panel: ANA and extractable nuclear antigens, ANCA (MPO and PR3), rheumatoid factor, cryoglobulins (sent and transported at 37 degrees), complements C3 and C4, hepatitis B and C, HIV, anti-MAG antibody, serum free light chains, and lactate dehydrogenase. A CT of the chest, abdomen, and pelvis for malignancy and lymphadenopathy. Methylmalonic acid and homocysteine to exclude functional B12 deficiency [2].

Treat the vasculitic neuropathy urgently. Once the biopsy is obtained, commence intravenous methylprednisolone 1 g daily for 3 to 5 days followed by oral prednisolone 1 mg per kg per day, with intravenous cyclophosphamide pulses for severe disease [3]. Add co-trimoxazole for pneumocystis prophylaxis, a PPI for gastric protection, and calcium and vitamin D for bone protection. Monitor full blood count, renal function, and urinalysis.

Manage the foot ulcer. Urgent podiatric and vascular assessment: debridement, offloading with a total contact cast, ankle-brachial index and duplex ultrasound or CT angiography for peripheral arterial disease, wound swab and culture, and antibiotics for infection. The ulcer precedes 85 per cent of diabetes-related amputations and is preventable [1].

Optimise glycaemic and cardiovascular risk. Intensify diabetes therapy, add or up-titrate a statin and antihypertensive, and counsel on smoking cessation. Replace B12 if methylmalonic acid is elevated. [1]

Control neuropathic pain. First-line pregabalin (75 mg twice daily, titrate to 150 to 300 mg twice daily) or duloxetine (30 mg then 60 mg daily) for the burning pain; short-term opioid analgesia for the acute vasculitic pain, which will improve with immunosuppression [5].

Characterise the paraprotein. If cryoglobulins and hepatitis C are positive, treat the cryoglobulinaemic vasculitis (pegylated interferon and ribavirin or direct-acting antivirals for hepatitis C, with rituximab for severe vasculitis). If anti-MAG is positive, the pattern is atypical and the paraprotein is likely incidental to the mononeuritis multiplex. A bone marrow biopsy is indicated if the paraprotein is significant or haematology parameters are abnormal. [1]

Rehabilitation. An ankle-foot orthosis for the right foot drop, physiotherapy for gait retraining and strengthening, occupational therapy for a home safety assessment, and falls prevention advice. [1]

Discussion questions

Examiner: "How do you classify this neuropathy?" [1]

Along the four axes. Fibre type: mixed sensorimotor with autonomic involvement. Distribution: there are two superimposed patterns — a chronic distal symmetric (length-dependent) polyneuropathy, and a subacute mononeuritis multiplex affecting the right peroneal and ulnar nerves. Time course: chronic (3 years) for the symmetric component and subacute (6 weeks) for the mononeuritis multiplex. Pathology (pending NCS): the diabetic DSPN is expected to be axonal, and the mononeuritis multiplex is expected to show axonal mononeuropathies consistent with vasculitic infarction. The classification immediately partitions the differential and directs the investigation [2].

Examiner: "Why do you suspect vasculitis rather than a diabetic mononeuropathy?" [1]

Several features favour an independent vasculitic process over a diabetic microvasculopathy. First, the mononeuritis multiplex involves two separate nerves (peroneal and ulnar) evolving in a stepwise, asynchronous fashion over weeks — the classic vasculitic pattern. Second, the systemic symptoms (weight loss, night sweats) and the raised CRP indicate a systemic inflammatory process. Third, the IgM paraprotein raises the possibility of cryoglobulinaemic vasculitis. Diabetic mononeuritis can mimic this, but the systemic features and the paraprotein demand a biopsy and a systemic workup to exclude an independent, treatable vasculitis. [1]

Examiner: "What is the role of the B12 level, and what would you do?" [1]

A B12 of 220 pmol per L is borderline, and functional B12 deficiency can occur with a normal serum level, particularly in metformin-treated patients (metformin impairs B12 absorption in up to 30 per cent of long-term users). I would check methylmalonic acid and homocysteine — elevated levels confirm functional deficiency. Given the safety of B12 replacement, I would commence parenteral hydroxocobalamin empirically while awaiting the results, because B12 deficiency neuropathy is partly reversible if caught early but becomes permanent. [1]

Examiner: "How would you manage his pain?" [1]

The chronic burning pain of the diabetic DSPN warrants first-line therapy with a gabapentinoid (pregabalin) or a serotonin-noradrenaline reuptake inhibitor (duloxetine), or a tricyclic antidepressant (amitriptyline), guided by comorbidity [5]. I would favour duloxetine (given his orthostatic symptoms make a tricyclic less suitable, and it also addresses any depressive component) or pregabalin. The acute severe pain of the vasculitic neuropathy may require short-term opioid analgesia and will improve with immunosuppression. I would avoid long-term strong opioids.

Short case — focused lower limb neurological examination

Instruction

"Examine this patient's lower limbs. He has a peripheral neuropathy." [1]

Systematic examination routine

1. End of bed inspection. Assess for muscle wasting (especially distal — the inverted champagne-bottle leg of CMT, or the peroneal wasting of any axonal neuropathy), foot deformity (pes cavus, hammer toes, claw toes), scars, ulcers, calluses, and the presence of an ankle-foot orthosis or walking aid. Note any fasciculations.
2. Tone. Usually normal or reduced in a neuropathy. Check for spasticity to exclude an upper motor neuron component.
3. Power. Test proximal muscle groups (hip flexion, extension, abduction and adduction; knee extension and flexion) and distal muscle groups (ankle dorsiflexion and plantarflexion; inversion and eversion; toe flexion and extension), with attention to a foot drop (peroneal nerve, L5). Use the MRC scale 0 to 5.
4. Reflexes. Test the knee jerks (L2 to L4) and ankle jerks (S1), using the Jendrassik reinforcement manoeuvre (the patient hooks their hands together and pulls) if they appear absent. Also test the plantar response.
5. Coordination. Heel-shin testing on each side.
6. Sensation. Pinprick and light touch (assess for a stocking-distribution loss and find the proximal sensory boundary), temperature (often paralleling pinprick), vibration (128 Hz tuning fork at the great toe, moving proximally to the malleolus and tibial tuberosity to find the level), and joint position sense at the great toe.
7. Gait. Observe the normal gait, then heel-toe (tandem) walking, then the Romberg test (stand with feet together, eyes open, then eyes closed — a fall or sway with eyes closed is a positive Romberg, indicating sensory ataxia from loss of proprioception). [1]

Key signs this patient demonstrates

• Distal muscle wasting and a right peroneal distribution weakness (foot drop).
• Absent ankle reflexes bilaterally, even with reinforcement.
• Stocking-distribution sensory loss to pinprick, temperature, and vibration to the mid-shin.
• Impaired joint position sense at the great toes.
• Sensory ataxia with a positive Romberg and a broad-based, high-stepping gait.
• A painless foot ulcer under the right first metatarsal head (indicating loss of protective sensation). [1]

Presentation template

"Doctor, on lower limb examination there is distal muscle wasting, a right foot drop with profound weakness of ankle dorsiflexion and toe extension (MRC grade 1) and preserved plantarflexion, consistent with a right peroneal nerve lesion. Ankle reflexes are absent bilaterally, even with Jendrassik reinforcement. There is a stocking-distribution loss of pinprick, temperature, and vibration to the mid-shin bilaterally, with impaired joint position sense at the great toes. Coordination is impaired on heel-shin testing. Gait is broad-based and high-stepping, and Romberg is positive. There is a painless ulcer under the right first metatarsal head. These findings are consistent with a distal symmetric sensorimotor polyneuropathy with sensory ataxia, with a superimposed right peroneal mononeuropathy. The most common cause is diabetic neuropathy, but the acute asymmetric mononeuropathy raises concern for a superimposed vasculitic process. I would proceed to nerve conduction studies and a blood panel to confirm the diagnosis and identify the cause." [1]

Discussion — the axonal-versus-demyelinating discriminator and CMT

Examiner: "How do nerve conduction studies distinguish axonal from demyelinating neuropathy?" [1]

In an axonal neuropathy, the primary abnormality is loss of axons, so the amplitudes of the compound muscle action potential and the sensory nerve action potential are reduced, while the conduction velocity is relatively preserved (because the surviving axons conduct normally). Needle EMG shows fibrillation potentials (active denervation) and large polyphasic motor unit potentials (reinnervation). In a demyelinating neuropathy, the primary abnormality is damage to the myelin sheath, so the conduction velocity is markedly slowed (below 70 per cent of the lower limit), distal latencies are prolonged, F-waves are prolonged or absent, and there is conduction block and temporal dispersion. The amplitude may be preserved unless there is secondary axonal loss. The distinction is the gatekeeper of the differential — axonal neuropathies are caused by diabetes, alcohol, B12, toxins, and drugs, while demyelinating neuropathies are caused by GBS, CIDP, CMT1, anti-MAG, and POEMS. [1]

Examiner: "What examination features would suggest Charcot-Marie-Tooth disease rather than an acquired neuropathy?" [1]

The features favouring CMT are a lifelong, slowly progressive course beginning in childhood or adolescence; a family history of similar problems; foot deformity (pes cavus, hammer toes, claw toes); the inverted champagne-bottle leg (marked distal muscle wasting below the knee); enlarged, palpable peripheral nerves; and lack of positive sensory symptoms (numbness and pain) despite clear sensory signs on examination [6]. In contrast, acquired neuropathies (diabetic, alcoholic, vasculitic) are typically of adult onset, progressive over months to years rather than decades, often painful, and without a family history or foot deformity. The absence of conduction block on NCS (uniform slowing) distinguishes CMT1 from acquired demyelinating neuropathies like CIDP.