CASE 1: A 22-year-old man presented after waking the previous day with numbness below his knees. There was no preceding illness and no relevant past history. He worked in retail, smoked cigarettes and drank moderate quantities of alcohol. His symptoms progressed over a few days to paraesthesia in the fingers, and difficulty with walking and performing fine tasks with his hands. He had no pain, no sphincter dysfunction and no autonomic symptoms. On examination, his cranial nerve function was normal. He walked with a broad-based gait, and Romberg's sign was positive. His muscle tone was flaccid, and he had mild, symmetrical, distal upper limb weakness (finger abduction, thumb abduction) with symmetrical mild proximal (hip flexion) and marked distal lower limb weakness. Deep tendon reflexes were absent and plantar responses flexor. Sensation to light touch and pinprick was reduced below the knees, vibration sense was absent below the anterior superior iliac spines and joint position sense absent below the ankles.

Initial investigations included normal full blood count, renal, liver, thyroid and bone profiles. Serum B₁₂ was normal at 333 ng/L (180–700). Cerebrospinal fluid (CSF) was acellular with protein 0.24 g/L (0.15–0.45) and CSF:serum glucose ratio >0.5. Nerve conduction studies showed slowed motor conduction velocities and delayed or absent F-waves, consistent with a demyelinating neuropathy. Sensory conduction was normal. MR scan of the whole spine was normal.

He started treatment with intravenous immunoglobulin 0.4 g/kg/day for 5 days on the basis of an acute demyelinating neuropathy consistent with Guillain–Barré syndrome. He admitted to using recreational nitrous oxide in the form of ‘whippits’—small pressurised canisters containing nitrous oxide used in whipped cream dispensers. His consumption had greatly increased over the six weeks before presentation, and he was using approximately 120 g (15 whippits) per day. Serum vitamin B₁₂ was normal, as were haematological indices; however, methylmalonic acid levels were markedly raised at 29 653 nmol/L (<280). We started treatment with intramuscular vitamin B₁₂. His sensory symptoms and strength gradually improved over the next six months, though he still requires a stick to walk.

CASE 2: A 27-year-old man was admitted to the emergency department with a 6-week progressive history of bilateral lower limb weakness. He had a history of recurrent patellar dislocations for which he attended the emergency department regularly. He also had a history of depression and self-harm, with cutting behaviours and parasuicide. He took no medication, drank no alcohol and did not smoke. He reported ‘allergies’ to paracetamol, opiates, tricyclic antidepressants, salt, pepper and sugar. On examination, his muscle tone was flaccid and he had symmetrical proximal and distal weakness of the lower and upper limbs with a glove and stocking sensory loss.

Initial blood tests were normal, including full blood count, serum B₁₂, folate and methylmalonic acid. His general practitioner had given a single dose of intramuscular vitamin B₁₂ the day before admission. CSF examination was normal. Nerve conduction studies were consistent with a primary demyelinating neuropathy with additional axonal loss (mean nerve conduction velocities in the upper limbs were 38–40 ms⁻¹ with normal compound muscle action potential amplitudes and delayed F-waves; there were profuse fibrillations in the lower limb muscles).

He was treated with intravenous immunoglobulin 0.4 g/kg/day for 5 days with some improvement, and he was discharged to rehabilitation care with normal upper limbs, able to walk with a frame. He re-presented 6 months later with a sudden, severe areflexic flaccid paraparesis with intermittent leg spasms; examination showed no upper motor neurone signs. On this occasion, serum vitamin B₁₂ was 108 ng/L (180–700), homocysteine 115 μmol/L (<30) and methylmalonic acid 1 180 nmol/L (<280). His nerve biopsy showed no primary demyelination but there was large myelinated fibre loss (hence slow conduction velocities) with multiple small vessel occlusions and ischaemic pathology without vessel infiltration. MR scan of brain and spinal cord showed hazy extensive white matter change in both cerebral hemispheres.

On this occasion, he admitted to dislocating his patella repeatedly and deliberately with a fist or a hammer in order to attend hospital and to receive nitrous oxide analgesia, which he had returned to doing following his first discharge. We immediately started rapid and high-dose replacement of B₁₂ on admission, but despite this he remains paraplegic and wheelchair user after 6 years of irregular follow-up.

CASE 3: A 23-year-old woman presented to the emergency department having woken with numbness on the lateral aspect of her knees and legs. This progressed down her feet and up her thighs and abdomen over two weeks, changing in character to a burning discomfort. She had a 6-year history of recurrent severe left flank and groin pain due to ‘nutcracker syndrome’ (compression of the renal vein between the abdominal aorta and superior mesenteric artery), leading to repeated attendances at the emergency department for pain relief. MR scan of brain and whole spine and nerve conduction studies were normal. CSF was acellular with protein and glucose within normal limits.

Over the next month, her symptoms progressed to involve her right hand; she developed Lhermitte's symptom, urinary urgency and required a stick to walk. On repeat examination, there was proximal upper and lower limb weakness, brisk tendon reflexes with pathological reflexes but absent ankle jerks and mute plantar responses. Her gait was ataxic with positive Romberg's sign. Joint position sense was absent to the knees and vibration sense to the hips.

She admitted to using nitrous oxide for analgesia at least twice per week, increasing in the weeks before admission, as well as occasional nitrous oxide ‘balloons’ recreationally from nightclubs. There was no other illicit drug use. She ate a normal diet. Serum B₁₂ was 217 ng/L (193–663) and homocysteine was raised at 42.8 ng/L (0–12). We started treatment with high-dose intramuscular B₁₂. Her gait and bladder function improved rapidly, and she subsequently recovered completely.