Subacute combined degeneration: a case of pernicious anaemia without haematological manifestations

Abstract

Vitamin B₁₂ deficiency can be caused by a diverse group of aetiologies. One of the less common of these is an autoimmune condition pernicious anaemia, so named after the most common physiological manifestation of B₁₂ deficiency: anaemia. However, B₁₂ is also necessary for nervous system function and its depletion can lead to dysfunction of the posterior columns of the spinal cord resulting in subacute combined degeneration (SCD). This disease, while debilitating in its acute phase, can usually be mostly if not fully reversed if caught early and treated appropriately. Early detection can prove challenging if there are no haematological manifestations of B₁₂ deficiency and the only guidance is the high index of suspicion. We present a case of pernicious anaemia leading to SCD without any clinical or laboratory findings of anaemia in this report.

Background

Cobalamin (vitamin B₁₂) is an essential vitamin required for DNA synthesis. This impairment especially affects cells that rapidly turnover, such as erythrocytes, thus leading to the traditional finding in cobalamin deficiency, a megaloblastic anaemia. Cobalamin is also essential for the synthesis of myelin, the insulating sheath surrounding axons of nerve cells. As such, a deficiency of cobalamin can produce damage to nerves due to decreased production of myelin sheath. Additionally, it is postulated but not proven that cobalamin deficiency may result in overexpression of myelinotoxic cytokines contributing to myelin damage.¹ Cobalamin, in coenzyme form, is only available from food derived from animal sources (meat, eggs and milk).²

The average total body content of cobalamin is 2–5 mg in adults, and complete discontinuation in absorption will deplete cobalamin stores in approximately 3–5 years. The recommended daily allowance of cobalamin for men, non-pregnant women, pregnant woman and children is 2.4, 2.4, 2.6 and 2.0 μg, respectively. A vegetarian diet may supply no more than 0.5 μg/day of cobalamin.^{2 3}

Cobalamin deficiency has many causes such as: decreased intake, malabsorption, medications, toxins and autoimmune (ie, pernicious anaemia) aetiologies. In western countries, pernicious anaemia, which results from reduced uptake secondary to autoantibodies that interfere with absorption, used to be by far the most common cause of cobalamin deficiency.However, malabsorptive states are rising in prominence due to the increased use of antacids and bariatric surgery.⁴

Subacute combined degeneration (SCD) is the spinal cord manifestation of B₁₂ deficiency and is characterised by paraesthesia, weakness, stiffness, numbness or tingling of limbs, ataxia and impaired vibration sense due to by selective demyelination of dorsal and lateral columns of the spinal cord. Classically, an ‘inverted V’ orientation of MRI hyperintensity in the posterior spinal cord can be appreciated.⁵

Prevalence of SCD has decreased since discovery of the aetiology due to therapeutic and prophylactic use of B₁₂ once a deficiency is demonstrated in the traditional workup for megaloblastic anaemia. Early diagnosis of SCD is very important as early intervention may inhibit irreversible neurological damage. We report the case of a 24-year previously healthy young woman presenting with typical physical examination and imaging findings of SCD without megaloblastic anaemia. Subsequent laboratory workup was consistent with the diagnosis of pernicious anaemia.

Case presentation

A 24-year-old woman with no significant medical history presented to the emergency department with concern for balance issues leading to falls as well as a few weeks of tingling in the extremities. One month back, the patient was involved in a minor motor vehicle accident wherein she suffered whiplash and hit the back of her head. Believing that she might be experiencing post concussive-related issues, she did not feel that the backward fall she experienced during army physical training 2 weeks after the accident was unusual. Thus, she did not seek medical treatment. A week later, the patient was seen in clinic for stocking/glove distribution numbness in the arms and legs. She reported at that time that this same numbness was present when she fell backward and hit her head during physical therapy. Her examination was reportedly normal at that time though a thorough neurological examination had not been completed. Concern persisted for changes related to concussion; thus, routine imaging and neurology referral were ordered but were not completed by the time of evaluation in the emergency department. The patient endorsed resolution of symptoms at follow-up a few days later that she attributed to a correction in her diet in the form of increased carbohydrates. This prompted a nutritional workup and the discovery of low B₁₂ levels. Despite the patient reporting resolution of paraesthesias, she continued to endorse difficulty walking; she denied frank numbness but felt like she was unclear where her feet were, causing her to feel off balance and impacting her ability to walk thus prompting her to come in to the emergency department for evaluation. She denied any other neurological deficits and denied a history of similar symptoms in the past.

Investigations

The patient was admitted to the neurology service for expedited workup of her symptoms. On examination, the patient appeared to initially have intact sensation with absent joint position sense at the feet, a positive Romberg, ataxia in the lower extremities, and an ataxic gait. Repeated and careful sensory testing did reveal reduced vibratory sensation at the feet. She demonstrated symmetric 1+reflexes in the biceps, triceps, and brachioradialis, 2+bilateral patellar reflexes, and 1+ankle jerks with mute plantar-extensor responses bilaterally. The remainder of the neurological examination was unremarkable. Due to the concern that her symptoms represented a demyelinating condition, an MRI of the brain, cervical spine and thoracic spine with contrast was completed and was remarkable for hyperintensity in the posterior aspect of the cervical cord at the level of C1–C5 (figure 1A) which was mildly contrast enhancing (figure 1B). Axial images through these levels revealed ‘inverted V sign’ at the dorsal aspect of the cord (figure 1C, D). MRI of the brain was normal.

Figure 1.

(A) Sagittal T2-weighted MRI showing hyperintensity in the posterior aspect of the cervical cord at the level of C1–C5. (B) A postcontrast T1-weighted image demonstrating mild enhancement corresponding with the T2 hyperintense signal shown in (A). (C) Axial T2-weighted MRI at the level of C2 and (D) at C4 both showing the ‘inverted V’ sign representing increased signal within the dorsal columns.

Lab workup was initially pertinent for haemoglobin 136 g/L (range 100–150 g/L), haematocrit 41% (range 34%–45%), meancorpuscular volume (MCV) 81 fL (range 80–98 fL), B₁₂ undetectable (range 211–946) and folate >20.0 ng/mL (range 7.3–20.0 ng/mL). Reflex testing for her B₁₂ deficiency was remarkable for homocysteine 81.1 μmol/L (range 0.0–15.0 μmol/L) and methylmalonate 2633 nmol/L (range 0–378 nmol/L). Iron studies were unremarkable with iron 115 μg/dL (range 30–160 μg/dL), total iron-binding capacity 375 μg/dL (range 286–515 μg/dL), iron saturation 31% (range 15%–50%) and transferrin 262 mg/dL (range 200–400 mg/dL). To exclude additional causes of myelopathy, copper was checked and found to be 115 μg/dL (range 72–166 μg/dL) and vitamin E was 8 mg/L (range 5.9–19.4 mg/L). She had undetectable tissue transgluaminase IgA and rapid plasma regain was negative. In investigating her B₁₂ deficiency, she was found to have high antiparietal cell antibody 35.0 units (range 0.0–20.0 units) and elevated intrinsic factor (IF) blocking antibody 17.3 unit/mL (range 0.0–1.1 unit/mL).

Treatment

The patient was started on daily B₁₂ injections at 1 mg. After a week, the patient was instructed to take 1 mg B₁₂ injections every other day. After that, the patient was instructed to take 1 mg B₁₂ injections every week for a month. She was then instructed to continue with 1 mg B₁₂ injections every month indefinitely. A course of physical therapy was recommended but the patient did not attend due to rapid improvement.

Outcome and follow-up

The patient was seen for follow-up about 6 weeks after initial presentation. She reported almost full resolution of symptoms after about 2 weeks on B₁₂ therapy. She was seen by a gastroenterologist who performed a survey oesophagogastroduodenoscopy and ruled out any evidence of gastric metaplasia or Helicobacter pylori. On examination, the patient’s ataxia and gait had greatly improved as had the patient’s vibratory sensation and joint position sense. She had no more falls.

Discussion

There are multiple aspects of this case that are of interest. First, this patient was an active duty soldier and was able to make it through regular group physical training without her ataxia being noticed. Second, when she was first seen and noted to be severely cobalamin deficient, she was not started on appropriate (intramuscular) supplementation right away, nor was a workup pursued. Presumably, a robust neurological examination was not undertaken either as if done it would likely have raised concern. This suggests that military midlevel providers may not be familiar with the complications of cobalamin deficiency and the necessary history, physical examination and work up required. Additionally, this patient noted that she was vegan for all of 2017 (but not for 2018) and thus likely deficient in cobalamin based on dietary restrictions. Dietary restrictions and risks may be pertinent information for unit leadership to know in order to prevent complications of vegetarianism and veganism. Also, cobalamin supplementation should perhaps be considered in vegan or vegetarian ‘meals ready to eat’.

Ninety-nine per cent of patients with haematological or neurological manifestations consistent with cobalamin deficiency will have cobalamin levels lower than the lower limit of normal. Conversely, 10% of cobalamin-deficient patients may have normal serum levels.² Increased methylmalonic acid and homocysteine concentrations are associated with cobalamin deficiency, and may be elevated even before cobalamin deficiency is detected.

Paraesthesia, weakness, stiffness, numbness or tigling of limbs, ataxia and impaired vibration sense are some of the most common clinical symptoms in SCD. T2 MRI findings classic show symmetric hyperintensity in the dorsal or dorsal and lateral columns due to demyelination, usually in the lower cervical and upper thoracic spine The classic axial view shows bilateral paired areas known as the inverted V.⁶ Involvement of anterior columns has been reported but is exceedingly rare.⁷ If addressed early, symptoms and MRI findings can resolve with treatment, but the degree of recovery depends on the amount of damage and the duration of illness.⁸

Neurological symptoms can occur in the absence of haematological abnormalities, although megaloblastic anaemia is generally an early common sign. Haematological disease can vary from incidentally increased MCV and hypersegmented neutrophils to severe anaemia with symptoms. Some studies have suggested that the severity of haematological changes does not correlate with degree of neurological complications which appears to be the case in this particular patient.⁹ In more recent years, neurological disease appears to have become more common while anaemia has become more mild or even absent. Only a portion of cobalamin-deficient patients have a classic megaloblastic anaemia and hypersegmented neutrophils appreciated on laboratory analysis.

Pernicious anaemia, traditionally the most common cause of low cobalamin levels, is due to IF deficiency. Pernicious anaemia can have both antigastric parietal cell antibodies and IF antibodies. Antigastric parietal cell antibodies can lead to gastric parietal cell atrophy and lead to decreased secretion of IF as well as decreased acid production. The incidence of pernicious anaemia is 25/1000 and generally affects patients 60 years or older.

Other risk factors for vitamin B₁₂ deficiency exist including gastric surgery, chronic pancreatitis, bacterial overgrowth, parasitic infection, medications and vegetarian or vegan diets.² Vegetarians and vegans may have overt or subclinical cobalamin deficiency and are advised to take B₁₂ supplementation.

The differential for SCD from cobalamin deficiency includes vitamin E deficiency, HIV, copper deficiency, infectious myelitis and multiple sclerosis. Vitamin E deficiency is rare but may present with similar imaging findings. HIV infection can cause a vacuolar myelopathy and can mimic SDC, in that dorsal and lateral columns are primarily affected. Spinal cord atrophy can be seen in the chronic stage of disease.¹⁰ Copper deficiency myelopathy may have clinical and imaging characteristics similar to SCD from B₁₂ deficiency, but low serum copper and ceruloplasmin levels will rule out the diagnosis.⁵

Early diagnosis of SCD is very important, as early intervention may avoid irreversible neurological damage. Extensive B₁₂ deficiency myelopathy has been defined as more than seven spinal segments involved. In one analysis, of 24 patients with greater than or equal to 7 spinal segments involved, only 1 patient had complete clinical recovery. This study notes worse prognosis in SCD which is associated with: more spinal segments involved, a sensitivity level on examination, present Romberg sign (a reflection of severe injury to heavily myelinated sensory axons in the posterior columns resulting in blockade of sensory impulses from the lower extremities) and present Babinski sign (is due to damage in corticospinal tract fibres). Age <50 and early treatment were associated with better prognosis.

Of patients who completely recovered from SCD, the average duration of illness was 6 weeks. Patients who only had partial improvement with cobalamin therapy had an average illness duration of 12 weeks. Most of the patients in this study had pernicious anaemia as the aetiology of their B₁₂ deficiency. In this study, 85% of patients had anaemia, macrocytosis and decreased B₁₂ levels. Shorter duration of illness was associated with improved likelihood of reaching complete resolution of SCD. The absence of anaemia was associated with higher rates of resolution of neurological deficits after B₁₂ therapy.¹¹ Most patients will have persistent neurological deficits, and improvement varies by severity and duration of illness.¹²

Learning points.

• Macrocytic anaemia is the most common manifestation of B₁₂ deficiency but is not always present in patients with symptomatic B₁₂ deficiency.

• Symptoms of subacute combined degeneration are not always as simple as reduced sensation.

• Falls and impaired balance in an otherwise healthy young patient should prompt immediate neurological evaluation to better catch subtle signs of proprioceptive loss.

• A vegan diet places patients at risk for B₁₂ deficiency and as such must be supplemented with cobalamin.