Primary progressive multiple sclerosis to be treated with ocrelizumab: a mistaken case of cobalamin deficiency

Abstract

Cobalamin (vitamin B₁₂) deficiency often manifests with neurologic symptoms and may rarely mimic multiple sclerosis (MS) among other neurological disorders. However, MRI changes associated with cobalamin deficiency are typically spinal predominant and distinct from MS-related changes. We report a case of a patient with cobalamin deficiency who was recommended by her primary neurologist to commence treatment with ocrelizumab, a potent anti-CD20 B-cell depleting monoclonal antibody, after being diagnosed with primary progressive MS. However, cervical spine MRI demonstrated changes classical of cobalamin deficiency including ‘inverted V sign’ signal hyperintensity and following parenteral cobalamin supplementation her neurological symptoms quickly and dramatically improved.

Background

Despite evolving MRI techniques and diagnostic criteria, multiple sclerosis (MS) remains an easily misdiagnosed disorder. There is now a vast armamentarium of disease modifying therapies (DMTs) for relapsing remitting MS. The first Food and Drug Administration (FDA)-approved DMT for primary progressive multiple sclerosis (PPMS), ocrelizumab, became available in the USA in 2017. Because treatment with ocrelizumab carries risk of serious complications, accurate diagnosis of PPMS is extremely important. PPMS is characterised by gradual neurologic decline from the outset rather than relapses with recovery, making diagnosis challenging. Cobalamin deficiency often presents with overlapping symptoms to PPMS, including gait ataxia, sensory dysfunction, and cognitive impairment. Herein, we report the case of a patient planned to commence ocrelizumab for suspected PPMS.

Case presentation

A 69-year-old Caucasian woman presented to our MS clinic in Autumn 2017 following a recent diagnosis of PPMS by her primary neurologist. She had a long-standing history of falls and migraine. In early 2017, she began experiencing bilateral hand numbness and paresthesia that spread to her elbows. She developed mild hand and leg weakness, Lhermitte’s sign, head tremors, slurred speech, impaired concentration, and mild urinary urgency and hesitancy. Her symptoms progressed such that within a few months she required a cane. At the time of assessment in our clinic her medications included calcium supplements, vitamin D₃, lorazepam, meloxicam, a multivitamin and gabapentin 300 mg daily. She had no relevant prior surgical history.

Investigations

Around this time, the patient’s cobalamin level was low (56 pg/mL; normal >180), and she received 1000 μg of cobalamin intramuscularly twice, 2 months apart, without benefit. In addition, cervical spine MRI from the same time period showed T2 hyperintensity extending from C4 to C6—with changes typical of cobalamin deficiency (figure 1A,B). However, the possibility of MS was pursued due to white matter changes on the brain MRI, although these were non-specific (figure 1C).

Figure 1.

Cervical spine and brain MRI. (A) Dorsal cord hyperintensity on sagittal T2-weighted images extending from C4 to C6. (B) Corresponding axial T2 sequences revealing symmetrical dorsal column hyperintensities giving the appearance of an ‘inverted V sign.’ (C) Non-specific white matter hyperintensities on axial fluid attenuated inversion recovery brain MRI sequences.

Nerve conduction studies, including a somatosensory evoked potential study, were normal, and anti-aquaporin-4 antibodies were negative. Cerebrospinal fluid (CSF) constituents were normal. Immunoglobulin G index was normal and oligoclonal IgG bands were not detected. In Summer 2017, she received a 5 day course of intravenous methylprednisone 1 g daily followed by an oral prednisone taper without improvement. She was then diagnosed with PPMS and recommended ocrelizumab by her primary neurologist.

In our clinic, she reported increasing hand weakness and Lhermitte’s phenomena. Neurological examination exhibited head tremor, mild left upper extremity and bilateral lower extremity spasticity, and exaggerated deep tendon reflexes. She had a mild pyramidal pattern of weakness in the upper and lower extremities, sensory level at C3 and severely impaired vibration and proprioception in all limbs. She required a cane and had a high stepping gait. Romberg sign was positive.

Differential diagnosis

Notably, repeat cobalamin level (4 months after last cobalamin injection) remained low at 97 pg/mL and anti-intrinsic factor (IF) antibodies were positive. This very low cobalamin level is considered diagnostic for cobalamin deficiency and testing for methylmalonic acid or homocysteine was not necessary.¹ Haemoglobin and mean corpuscular volume were normal and the patient had no history of gastrointestinal illness, with the exception of transient abdominal cramps and diarrhoea following steroid treatment. Given these results and the patient’s symptoms and history, she was diagnosed in our centre with cobalamin deficiency.

The aetiology of the cobalamin deficiency in this case was felt to be autoimmune due to the presence of IF antibodies in the absence of recent cobalamin supplementation (which can cause false positive anti-IF antibodies) and lack of other causes. The patient did not have dietary restrictions and consumed animal products. She had no gastrointestinal symptoms prior to disease onset, no history of bariatric surgery and no known exposure to nitrous oxide, metformin or proton pump inhibitors.

Treatment

The patient was treated aggressively with monthly intramuscular injections of 1000 μg cobalamin and twice daily 1000 μg cobalamin tablets sublingually.

Outcome and follow-up

Three to four weeks after beginning treatment, the patient reported dramatic improvement in gait, urinary symptoms and cognition. Two months later, she reported sustained improvement with no falls and no need for a walking aid. She remains stable on the same regimen of cobalamin replacement.

Discussion

This case highlights the importance of careful clinical assessment and appropriate interpretation of laboratory and radiological findings in the differential diagnosis of myelopathy. The patient exhibited some MS symptoms, including mobility impairments that increased steadily over months, as is commonly observed in PPMS.² However, there were many features in this case suggesting that an alternative aetiology was more likely. The mean age of onset of PPMS is approximately 40 years²; MS onset at 69 years old is uncommon. In addition, CSF was negative for oligoclonal bands and IgG index was normal.

Furthermore, the radiological findings were atypical of MS. Brain MRI changes were non-specific and lacked either the required characteristics or typical locations of MS lesions according to current diagnostic criteria for MS.³ Moreover, in the absence of oligoclonal bands in the CSF, two spinal cord lesions are required for a PPMS diagnosis³—this patient had only one lesion. A striking finding was the T2 hyperintense signal on spinal MRI involving the posterior funiculus bilaterally, giving the appearance of an ‘inverted V sign’. This is well described in subacute combined degeneration of the spinal cord caused by cobalamin deficiency, whether nutritional or functional (eg, due to nitrous oxide poisoning).^{4 5} This sign is also seen in copper deficiency⁶ and reported in Chiari I malformation.⁷

Cobalamin-associated myelopathy is characterised by subacute combined degeneration, and manifests on MRI as symmetrical, T2 hyperintensity, typically affecting the dorsal and/or lateral corticospinal columns of the spine.⁸ Due to anti-IF antibodies, this patient will continue cobalamin supplementation indefinitely. Cobalamin repletion dosage is often 1000 μg sublingually or intramuscularly once daily for 7–10 days, then once weekly for 1 month, then once monthly indefinitely.⁹ Of note, this patient’s symptoms progressed initially when she received inadequate replacement.

In summary, this case highlights the importance of carefully considering the differential aetiologies of progressive myelopathy when diagnosing PPMS. This is especially relevant with the advent of PPMS treatments that carry risk of serious complications. Cobalamin deficiency should always remain high in the differential diagnosis of neurologic symptoms. In addition to mimicking MS, symptoms of cobalamin deficiency can present similarly to those of neuromyelitis optica spectrum disorders, as described in a case by Tornes and colleagues.¹⁰ Timely and accurate diagnosis of cobalamin deficiency is very important, as delays in diagnosis can lead to irreversible neurologic symptoms, as described in two cases by Svenson.¹¹ High doses of cobalamin supplementation may be required to achieve therapeutic response.

Patient’s perspective.

The whole ordeal started at the end of February 2017. I was in the kitchen getting ready for a birthday party when all of a sudden both of my hands went numb. The following month I had visited my family doctor and they did not know what was going on. So they had me go get X-rays to see if my neck had anything causing it. After 3 days after I went to get X-rays, my family doctor informed me that everything was normal. I had started struggling with walking, talking and being unable to think straight. I knew something was not right, so I went ahead and contacted a neurologist. When I went to my appointment with the neurologist, he went ahead and did a spinal tap. At the conclusion of the appointment he had ordered bloodwork and an MRI. The following appointment I had with the neurologist, he informed me that I had multiple sclerosis (MS). The reason for this was due to the fact that when my MRI came back, my neurologist noticed lesions in my brain and spine. What ever I had was so bad that I had started using a cane. In just a couple months both me and my family were upset. I went back to my neurologist and he referred me to get infusions. At the end of June 2017 I began to get the infusions. The infusions started on Monday and ended on Friday, for five consecutive days. Following the infusions my doctor prescribed me prednisone. For the first 4 days the dosage was 50 mg and then the following 4 days it was reduced to 40 mg. Afterwards I slowly got off the medicine all together. A week after being off prednisone, I started having massive stomach pains, symptoms included loose stool and bleeding. It got so bad I ended up going to the hospital for 4 days. Once in the hospital, I had been diagnosed with colitis. Once I was released from the hospital I had went to see my gastrointestinal doctor, and they confirmed that I no longer had colitis. This was the last straw. I decided to get a second opinion on my diagnosis. I had gotten an appointment with a neurologist at John Hopkins Department of Neurology— MS. When I went to my appointment with the neurologist, the neurologist concluded after looking over everything, I did not have MS. He did an eye test and a blood test. The eye test came back clear, but the blood test came back with something concerning. The blood test showed that my B₁₂ levels were low, at 192. He prescribed a 2000 mg supplement, administered under the tongue every morning. Following this I began getting B₁₂ shots monthly. My B₁₂ levels stayed steady at 1500. After a few month my doctors decided to drop the shots to every other month. But once this started my B₁₂ levels dropped once more. Once this started happening they did bloodwork and found out that I have intrinsic factor. I have been through a lot from February 2017, up until now. I have had seven MRIs and six X-rays and not to mention the multiple blood tests I have done. I have been through a lot. Its gone as far as getting my C4 to C6 vertebrae removed, because doctors thought that this was the reason my hands went numb. It was later due to the fact that it was carpal tunnel causing the numbness in my hands. So now I wear wrist braces at night, and so far everything is normal.

Learning points.

• Many diseases mimic multiple sclerosis (MS). In light of treatments that carry risk of serious complications, accurate diagnosis of MS is very important.

• Cobalamin deficiency may present with symptoms commonly observed in MS.

• Cobalamin-associated myelopathy is characterised by subacute combined degeneration of the spinal cord.

• High doses of cobalamin supplementation may be required to achieve therapeutic response.