Subacute combined degeneration of the cord
Description
- Vitamin B12 (cobalamin) deficiency myelopathy - symmetrical demyelination of the DORSAL and LATERAL columns, beginning in the mid-thoracic cord
- "Combined" = dorsal columns (sensory ataxia) + corticospinal tracts (spasticity)
- Often with a coexisting peripheral neuropathy - which is what produces the classic mixed picture
- *The signature examination finding: extensor plantar responses with ABSENT ankle jerks*
- Also caused by nitrous oxide (recreational "nangs", or repeated anaesthetic exposure) - increasingly the commonest cause seen in young people
- Copper deficiency produces a clinically indistinguishable myelopathy - always check both
Epidemiology
- B12 deficiency in ~5-20% of adults over 60; neurological involvement in a minority
- Neurological features occur without anaemia in up to 25% - *a normal full blood count does not exclude it*
- Nitrous oxide-related SCDC: young adults, rising sharply; often severe at presentation
- Pernicious anaemia: F>M, onset >60, more common in people of Northern European ancestry
Aetiopathogenesis
Causes of B12 deficiency
- Malabsorption
- Pernicious anaemia - autoimmune gastric atrophy, anti-intrinsic factor and anti-parietal cell antibodies
- Gastrectomy or bariatric surgery; terminal ileal disease or resection (Crohn); coeliac disease
- Bacterial overgrowth, fish tapeworm (Diphyllobothrium), tropical sprue
- Drugs - metformin, PPIs, H2 antagonists (chronic use)
- Dietary - strict vegan diet, poverty, alcohol misuse
- Nitrous oxide - irreversibly oxidises the cobalt of cobalamin, inactivating methionine synthase
- Serum B12 may be entirely NORMAL - the functional deficiency is at the enzyme, so measure homocysteine and methylmalonic acid
- Inherited: transcobalamin II deficiency, Imerslund-Grasbeck
Mechanism
- B12 is a cofactor for methionine synthase (homocysteine -> methionine) and methylmalonyl-CoA mutase
- dec methionine -> dec S-adenosylmethionine -> impaired methylation of myelin basic protein and phospholipid
- Accumulated methylmalonyl-CoA -> abnormal odd-chain fatty acid incorporation into myelin
- -> vacuolar demyelination of the dorsal and lateral columns, then axonal loss
- *Once axonal loss occurs the deficit is permanent - which is why treatment is urgent, not routine*
Diagnosis
Clinical
- Symmetrical distal paraesthesia in the feet, progressing upward - usually the first symptom
- Dorsal column: loss of vibration and joint position sense, positive Romberg, sensory ataxia with a stamping gait, Lhermitte sign
- Corticospinal: spastic paraparesis, weakness, extensor plantar responses
- Peripheral neuropathy: absent ankle jerks
- Autonomic: bladder and bowel dysfunction, impotence
- Also: optic atrophy, dementia and psychiatric change ("megaloblastic madness"), glossitis, angular stomatitis, lemon-yellow skin pallor
- Pain and temperature sensation are relatively preserved - a dissociated sensory loss**
The reflex patterns to know
| Pattern | Causes |
|---|---|
| Extensor plantars + ABSENT ANKLE JERKS | Subacute combined degeneration, conus medullaris lesion, combined UMN lesion with cauda equina compression or peripheral neuropathy, tabo-paresis (neurosyphilis), Friedreich ataxia, diabetes (uncommonly), adrenoleukodystrophy/metachromatic leukodystrophy |
| Extensor plantars + ABSENT KNEE JERKS | Combined peripheral neuropathy and pyramidal lesion (e.g. a diabetic with a stroke), motor neurone disease, conus medullaris or cauda equina lesion, tabes dorsalis, subacute combined degeneration |
Dorsal-column-predominant (dissociated) sensory loss with preserved pain and temperature
- Subacute combined degeneration of the cord
- Brown-Sequard syndrome - ipsilateral leg
- Spinocerebellar degeneration such as Friedreich ataxia
- Multiple sclerosis
- Tabes dorsalis
- Sensory neuropathy or ganglionopathy (paraneoplastic, Sjogren, cisplatin, B6 excess)
- Peripheral neuropathy from diabetes or hypothyroidism
Investigations
- Serum B12 - insensitive; low-normal values do not exclude deficiency, and it is often normal in nitrous oxide toxicity
- *Homocysteine and methylmalonic acid are the functional markers - both rise in B12 deficiency; only homocysteine rises in folate deficiency*
- Also active B12 (holotranscobalamin)
- FBE and film - macrocytosis, hypersegmented neutrophils; normal in up to 25% with neurological disease
- Copper and caeruloplasmin (and zinc - excess zinc causes copper deficiency), folate, TFT, HIV, syphilis serology
- Anti-intrinsic factor antibody (specific, insensitive) and anti-parietal cell antibody (sensitive, non-specific); gastrin
- MRI whole spine with gadolinium - "inverted V" or "dorsal column" T2 hyperintensity in the posterior columns, usually cervical/upper thoracic, over several segments
- Also excludes compressive myelopathy - which is the diagnosis that must not be missed
- Nerve conduction studies - axonal sensorimotor neuropathy
- Ask directly about nitrous oxide use - patients rarely volunteer it
Management
A. Replace B12 - urgently, and do not wait for confirmation
- Hydroxocobalamin 1000 microgram IM on alternate days until improvement (or for ~2 weeks), then monthly for life in neurological disease
- Loading is more intensive than for uncomplicated anaemia; some units give it daily for the first week
- High-dose oral B12 (1000-2000 microgram daily) is adequate for maintenance in dietary deficiency but is NOT appropriate for acute neurological disease
- *Give B12 BEFORE folate[[c2]] - folate alone in an untreated B12-deficient patient precipitates or worsens subacute combined degeneration*
- Check potassium in the first week of replacement - rapid erythropoiesis causes hypokalaemia
B. Treat the cause
- Stop nitrous oxide completely - counsel about neurological permanence; drug and alcohol referral; methionine and B12 both required
- Pernicious anaemia -> lifelong parenteral B12, and screen for other autoimmune disease
- Coeliac disease, Crohn, bacterial overgrowth - treat the gut disease
- Review metformin and long-term PPI; supplement rather than stop where the drug is needed
- Correct copper deficiency if present (oral or IV copper; stop zinc supplements)
C. Supportive
- Physiotherapy and occupational therapy - gait retraining, balance, home modification
- Falls prevention - sensory ataxia is worse in the dark; night lighting, walking aid
- Neuropathic pain management; spasticity (baclofen)
- Bladder and bowel management; pressure care
- Driving assessment if proprioception is significantly impaired
- Dietitian; alcohol and nutrition support
Associations
- Pernicious anaemia and its autoimmune company - autoimmune thyroid disease, type 1 diabetes, vitiligo, Addison disease, coeliac disease
- Gastric carcinoma and gastric carcinoid - increased risk in pernicious anaemia
- Bariatric surgery, gastrectomy, terminal ileal Crohn disease or resection
- Metformin, proton pump inhibitors, H2 antagonists
- Nitrous oxide use - recreational and occupational
- Alcohol misuse and malnutrition; vegan diet
- Copper deficiency myelopathy - the clinical mimic; also from zinc excess and bariatric surgery
- HIV and tabes dorsalis (neurosyphilis) - both in the differential
Natural history & complications
- Recovery depends almost entirely on the duration of symptoms before treatment
- Symptoms <3 months -> substantial or complete recovery in most
- Symptoms >6-12 months -> significant permanent deficit
- Improvement begins within days to weeks and continues for 6-12 months; what has not recovered by 12 months is generally permanent
- Paraesthesia and cognitive change respond best; spasticity, ataxia and bladder dysfunction respond least
- Nitrous oxide-related disease can be severe, and relapses immediately if use resumes
Complications
- Permanent spastic paraparesis and sensory ataxia; wheelchair dependence
- Falls and fractures
- Neurogenic bladder, recurrent UTI
- Optic atrophy and visual loss
- Cognitive impairment and psychiatric disturbance - may not fully reverse
- Megaloblastic anaemia and its consequences; hypokalaemia during replacement
- Pressure injury, contracture, depression
Monitor
- FBE and reticulocytes at 1 week (reticulocytosis confirms response), potassium in the first week
- B12 level and clinical response at 3 months; iron studies (a masked iron deficiency is often unmasked as erythropoiesis resumes)
- Neurological examination - power, tone, vibration, proprioception, gait
- Adherence to lifelong maintenance injections - the commonest reason for relapse
- Pernicious anaemia: symptoms of gastric malignancy, other autoimmune disease
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