Subacute Combined Degeneration of the Spinal Cord

Subacute combined degeneration of the spinal cord is a myelopathy of the dorsal columns and corticospinal tracts caused by vitamin B12 deficiency, or functional deficiency from nitrous oxide exposure. It is treatable, and early replacement prevents permanent deficit.

B12 deficiency affects about 6% of people under 60 years and up to 20% over 60 years. Neurological involvement occurs in a minority of those deficient, and subacute combined degeneration is rare, with a peak in older adults and in recreational nitrous oxide users aged 18 to 30.

Causes. Pernicious anaemia (commonest), gastric and ileal disease or surgery, metformin and proton pump inhibitor use, strict vegan diet, Diphyllobothrium infection, and nitrous oxide inhalation (inactivates B12).

Course. Progressive over weeks to months if untreated. Recovery is best when treated within 3 to 6 months, and may be incomplete after longer delay.

Pathophysiology.

B12 is a cofactor for methionine synthase and methylmalonyl coenzyme A mutase. Deficiency impairs myelin synthesis and causes vacuolation and demyelination of the dorsal and lateral columns of the spinal cord.

Raised methylmalonic acid and homocysteine are the markers of the metabolic block.

• Paraesthesia of the feet and hands, then loss of vibration and position sense, sensory ataxia and a positive Romberg test.
• Spastic paraparesis with extensor plantar responses; reflexes may be absent if peripheral neuropathy coexists.
• Lhermitte sign, bladder and bowel dysfunction, and sexual dysfunction.
• Cognitive change, depression, optic neuropathy and glossitis in some.
• Anaemia or macrocytosis in many, but neurological disease can occur with a normal blood count.

Red flags.

• Rapid worsening, urinary retention or new gait failure.
• Cognitive impairment, psychosis or visual loss.
• Cardiac signs of severe anaemia.

• Serum B12 (low or low normal), with methylmalonic acid and homocysteine when the level is borderline; holotranscobalamin when available.
• Full blood count and film, intrinsic factor and parietal cell antibodies, thyroid function and endoscopy where indicated.
• MRI of the cervical and thoracic spine: symmetrical T2 hyperintensity in the dorsal columns (the "inverted V" sign).
• Nerve conduction studies and somatosensory evoked potentials show slowed central conduction.
• Ask about nitrous oxide use; exclude copper deficiency, HIV, syphilis, multiple sclerosis and vitamin E deficiency.

Differential diagnosis. Copper deficiency myelopathy, multiple sclerosis, tabes dorsalis, HIV vacuolar myelopathy, compressive myelopathy, Friedreich ataxia, vitamin E deficiency and neuromyelitis optica spectrum disorder.

• Hydroxocobalamin 1 mg intramuscularly on alternate days until there is no further improvement, then 1 mg every 2 months for life when the cause persists. Maximum 1 mg in each injection. Monitor potassium in the first week of treatment in severe anaemia, full blood count and neurological recovery. Avoid in hypersensitivity to cobalamin; use caution in Leber disease (optic atrophy).
• Do not give folic acid alone because it can worsen neurological disease; give folic acid 5 mg orally daily only together with B12 if folate is also deficient. Maximum 5 mg daily. Monitor B12 and folate.
• Stop nitrous oxide use and give supportive substance misuse advice; if nitrous oxide caused the illness, give hydroxocobalamin 1 mg intramuscularly on alternate days, and consider methionine under specialist advice.
• Treat the cause: pernicious anaemia needs lifelong injections; treat malabsorption, review metformin and proton pump inhibitors and correct diet.
• Physiotherapy, gait aids, spasticity management and falls prevention; occupational therapy.
• Baclofen for disabling spasticity: 5 mg orally three times daily, increased by 5 mg every 3 days to a usual 30 to 75 mg daily. Maximum 100 mg daily. Monitor sedation, weakness and seizures; withdraw slowly. Reduce dose in renal impairment (creatinine clearance under 50 mL/min); avoid in peptic ulcer.
• Treat neuropathic pain as needed.

Monitoring. Check B12, full blood count and potassium at 1 and 4 weeks; review neurology at 3 and 6 months; yearly B12 injections thereafter.

Referral and escalation. Neurology and haematology; gastroenterology for malabsorption; addiction services for nitrous oxide misuse.

Special groups. Older adults: higher risk of missed diagnosis and falls. Pregnancy: B12 injections are safe. Vegans: lifelong supplementation.