Paraparesis after Nitrous oxide inhalation/myeloneuropathy due to Vit B12 deficiency

Causes of Vit B12 deficiency: pernicious anemia due to autoimmune parietal cell dysfunction, associated with defective gastric secretion and absence of intrinsic factor; inadequate dietary intake (vegans), atrophy of the gastric mucosa, parietal or total gastrectomy, functionally abnormal intrinsic factor, inadequate hydrolysis of dietary cobalamin, insufficient pancreatic protease, bacterial overgrowth in the intestine, terminal ileum disease, tropical sprue, genetic enzyme deficiencies (methylmalonic aciduria), tapeworm infestation, disorders of plasma transport of cobalamin, dysfunctional uptake and use of cobalamin by cells, drugs such as metformin, PPI, and nitrous oxide administration. 

Nitrous oxide (N2O) is widely used as a propellant in the food industry (whipped cream dispenser - whippet/whip-it).  It is also widely used as in anesthesia.  It is a potent antioxidant that has multiple deleterious effects on cobalamin metabolism.  In humans, the use of N2O is associated with neurologic and hematologic manifestations.  Patients with cobalamin deficiency may be particularly susceptible to brief exposures to nitrous oxide, which inactivates cobalamin-dependent methionine synthase and may cause a myeloneuropathy.  In healthy subjects, this side effects on the methionine synthase methlcobalamin complex may be well compensated for by the large vitamin B12 deficiency, even a short course of nitrous oxide anesthesia may deplete the few remaining stores.  

Symptoms:

• In pernicious anemia neurological manifestations reflect degeneration of myelin in dorsal and lateral columns of spinal cord, peripheral nerve, and cerebral dysfunction.  Myelopathy, peripheral neuropathy, and optic neuropathy are common neurologic complications of pernicious anemia.

• Weakness in both lower extremities, numbness in both feet, bladder dyscontrol, and erectile dysfunction. patellar hyper-reflexia (early on there is normal reflexes or hyporeflexia), ankle areflexia, bilateral extensor plantar responses.  

• Unsteady gait due to gait ataxia, loss of proprioception sense in 2nd toe and loss of vibration sensation for a 256 Hz but not 128 Hz tuning fork are the earliest signs of dorsolateral column involvement.  

• Lhermitte sign may be present.  In nitrous oxide there is reverse Lhermitte sign (electric shooting sensation goes up the spine)

• Confusion, irritability, cognitive dysfunction, perversion of taste and smell, diminished visual acuity, optic atrophy and impaired micturition.  

• Neuropsychiatric symptoms include fatigue, apathy, irritability, cognitive slowing, and forgetfulness. Acute psychosis from vitamin B12 deficiency can occur with or without other features of deficiency suggest subacute combined degeneration.

• Although several different manifestations of peripheral neuropathy can be seen in patients with vitamin B12 deficiency, the most common form is a length-dependent sensorimotor neuropathy, with axonal as opposed to demyelinating features. The neuropathy is most commonly painless and can be associated with other signs of vitamin B12 deficiency, including cognitive impairment and myelopathy. 

DDx:  Neurosyphilis, disseminated tuberculosis, HIV associated infections, SLE, neurosarcoidosis, acute disseminated encephalomyelitis, multiple sclerosis, nitrous oxide, vitamin B12 deficiency, vitamin D, E, copper, and folate deficiencies.  Malabsorption syndromes (UC).  

Laboratory and diagnostic:

• Low vitamin B12, elevated MMA, homocysteine levels

• anti-intrinsic factor-ab (specific) parietal cell abs, increased gastrin, decreased pepsinogen levels (specific for pernicious anemia).

• HIV, syphilis, TB-quantiferon, Vit B12, MMA, copper, zinc, folate, vit E

• CSF: ACE, syphilis, OCB, protein, glucose, MOG, MS labs.  Other infections (meningoencephalitides)

• EDX show an axonal sensorimotor neuropathy.

• MRI of C/T/L spine - posterior and lateral column hyperintensities.

• VEP for optic neuropathy

Treatment:

• Vitamin B12 1000 mcg IM injections daily for a week, then follow-up with weekly injection for 4 weeks, then monthly until symptoms resolve. Continue with daily PO vitamin B12 1000 mcg until symptoms resolve if intrinsic factor antibody is rule out.  Alternatively give Vit B12 1000 mcg IM injections daily for 5 days, then 1000 mcg IM monthly, if intrinsic factor ab is present. 

Copper  deficiency also mimic Vit B12 deficiency induced myelopathy:

• Tx:  2 mg IVPB daily x 5 days, then orally administered at a dose of 8 mg daily x 1 week, then 6 mg daily x 1 week, then 4 mg daily x 1 week, then 2 mg daily thereafter. F/up levels 

Vitamin B12 deficiency as a cause of polyneuropathy remains a common phenomenon.  Patients typically present with sensory neuropathy and a myelopathy called subacute combined degeneration (SCD) a term that is descriptive for the pathology of the dorsal column, cortical spinal tract, and peripheral nerves.  Patients typically lose vibration and joint position sense in the toes and ankles, hyperreflexia in the upper extremities and knees, and absent ankle reflexes.   Neuropathologically, patients have a large fiber neuropathy and atrophy of the dorsal column and the corticospinal tracts.  Hematologic studies show a megaloblastic anemia with an elevated MCV and hypersegmented PMN count.  Serum levels of Vit B12 below 100 pg/mL should be considered suspicious for the diagnosis. They should be considered suspicious for the diagnosis and should lead to further testing if the patient has a polyneuropathy.  Elevated MMA and homocysteine levels help to support the diagnosis. 

Copper deficiency causes a similar process as Vitamin B12 deficiency.  If the disease is severe or untreated for long periods, patients manifest lower extremity paresthesia, leg weakness, gait ataxia, and spasticity.  Similar to SCD, patients have myelopathy and peripheral neuropathy, clinically and electrodiagnostically.  The anemia associated with copper deficiency is microcytic and is associated with neutropenia and sometimes pancytopenia.  IV copper reverses the hematological, but not the neurologic manifestations of the illness.  Several cases of copper deficiency neuropathy and anemia have been described in patients who have since toxicity as high zinc levels lead to copper deficiency.  Some denture creams are known to contain large amounts of zinc and some patients were using large amounts of denture creams to secure their dentures.  For this reason patients with low copper levels should be screened for zinc toxicity. 

Subacute Combined Degeneration of the Spinal Cord - StatPearls - NCBI Bookshelf (nih.gov) 

Vitamn B12 deficiency