It’s Not What You Zinc!: A Case of Progressive Neurologic Disease
CASE
A 37-year-old woman with past medical history of anemia, cervical cancer, depression, and endometriosis presents to the ED after two years of progressive ascending weakness, paresthesias, and sensory deficits, now having new episodes of bowel and bladder incontinence.
2 ½ years ago she started having paresthesias in her bilateral feet, progressing to numbness in her entire legs bilaterally. 1 year ago, she began having progressive weakness in her bilateral legs to the point that she is now non-ambulatory. Around the same time, she began to have urinary overflow incontinence. Over the past month, she has had two episodes of bowel incontinence leading to her ED presentation. She also endorses new paresthesias and weakness of her bilateral hands and wrists over the past few months.
Extensive work-up at outside hospitals has been inconclusive. Most recently, 1 year ago at an OSH she had an MRI Brain and Total Spine significant only for a stable syrinx in her cervical spine unchanged from her previous MRI 2 years ago; lumbar puncture was performed and all CSF studies were normal; autoimmune and vitamin deficiency workup was normal. She was referred for outpatient EMG/NCS but notes that she was unable to go.
Physical Exam:
Neurologic exam:
Increased tone in the lower extremities, normal in upper extremities. No atrophy.
Diminished pinprick and fine touch sensation in the lower extremities without a sensory level or clear dermatomal distribution. Proprioception is abnormal in toes bilaterally.
Increased reflexes in the lower extremities and pectorals.
Severe bilateral lower extremity weakness distal > proximal, and moderate bilateral upper extremity weakness most significant in wrist extension.
Vital signs and physical exam were otherwise normal.
Neurology was consulted and recommended repeat MRI C/T/L Spine given worsening symptoms. In addition to previously findings, a subtle symmetric T2 hyperintensity was seen in the basilar cervical spinal cord from C2 to C4/5 (images in Figure 1, at end of case presentation).
On further interview, the patient endorsed chronically over-using a Zinc-containing denture glue due to unstable dentures. Labs revealed a pronounced copper deficiency of 17 mcg/dL (normal 70-175), low ceruloplasmin at 12 mg/dL (normal 14-40), and a high-normal zinc level of 118 mcg/dL (normal 60-130), consistent with copper deficiency secondary to chronic zinc overuse. Neurology believes the C-spine lesion on MRI is consistent with copper deficiency myelopathy (CDM), and that diagnosis explains the majority of her symptoms, with some functional disorder overlay. She was admitted to neurology for copper repletion, urinary catheter teaching, and PT/OT. Her condition improved during admission, most notable for increased strength in proximal muscle groups in bilateral lower extremities. Discharged home with copper supplementation, zinc-free denture glue and instructions to follow-up outpatient with neurology and dentistry, and avoid Zinc containing foods (oysters).
Figure 1: The patient's T2 C-Spine MRI (left) vs. typical T2 C-Spine MRI in copper deficiency myelopathy (right) [1]. Hyperintense lesions outlined in red.
Clinical Question: What is copper deficiency myelopathy (CDM), when should it be suspected, and how is it diagnosed and managed?
SUMMARY OF EVIDENCE/RECOMMENDATIONS
Epidemiology of Copper Deficiency Myelopathy
More common in fifth and sixth decade of life, more common in women (F:M ratio 3.6:1).[1]
Causes include upper gastrointestinal surgery (most commonly partial gastrectomy for peptic ulcer disease and bariatric surgery), zinc overload (most commonly from denture cream, also seen with zinc supplements), and malabsorption (mostly from celiac disease).[1,3,6,8]
Pathogenesis of Copper Deficiency Myelopathy
The myelopathy is suggested to be due to dysfunction of cytochrome-c oxidase, a copper-dependent enzyme. Other suggested mechanisms include dysfunction of the methylation cycle common to the synthesis of many molecules, including myelin proteins. [1,4,5]
Zinc excess leads to copper deficiency through upregulation of a chelator molecule, matallothionein. This molecule binds copper with a higher afficinity than zinc, and secludes the copper in enterocytes which are shed into the GI lumen and eliminated (Figure 2). [1, 2, 7, 10is of Copper Deficiency Myelopathy
Typical presentation is with gait difficulty, most commonly secondary to sensory ataxia and less commonly from spasticity. Other common symptoms include paresthesias in upper and lower limbs, with urinary incontinence/retention present in a minority of patients. [1-7]
Diagnostic work-up should be sure to rule out more dire causes of neurologic dysfunction including spinal cord compression, spinal epidural abscess, malignancy, meningitis, trauma, infarction or ischemia, CVA or hemorrhagic stroke; as well as common progressive neurologic illnesses such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and acute or chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP).[9]
Physical examination can show a spastic paraparesis. Depression of distal reflexes and sensory impairment in glove and stocking distribution is also reported, though less common.[1,4,5]
Cytopenias are common, most frequently anemia and leukopenia with some reported cases of thrombocytopenia.[1,7]
To diagnose CDM, serum copper levels must be low, ceruloplasmin levels are also often low. Serum zinc levels may be low, normal, or high based on the etiology of the copper deficiency. Urinary copper excretion is typically low, and urinary zinc is typically elevated.[1,4,5]
T2 hyperintense signal in posterior cervical and/or thoracic cord seen in 50% of cases. Classic T2 MRI findings shown in Figure 1 (above).[1,4,5]
Treatment of Copper Deficiency Myelopathy
Copper supplementation: typically orally or intravenously with subsequent switching to oral. Reported doses in literature are usually equivalent to 2 mg/day of copper.[1,7]
Treatment of underlying cause: stopping exogenous supply of zinc, gluten-free diet for celiac disease, reported cases of gastric bypass revision.[1,4,5,7]
Neurologic deficits improved in 50% of cases in one literature review, most commonly slight recovery of strength and mobility and reduction of sensory symptoms. No reports of full return to neurologic baseline.[1]
REFERENCES
1. Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol. 2010 Jun;257(6):869-81. doi: 10.1007/s00415-010-5511-x. Epub 2010 Mar 16. PMID: 20232210; PMCID: PMC3691478.
2. Nations SP, Boyer PJ, Love LA, Burritt MF, Butz JA, Wolfe GI, Hynan LS, Reisch J, Trivedi JR. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology. 2008 Aug 26;71(9):639-43. doi: 10.1212/01.wnl.0000312375.79881.94. Epub 2008 Jun 4. PMID: 18525032.
3. Mutti C, Bazzurri V, Tsantes E, Curti E, Parrino L, Granella F. Copper deficiency-associated myelopathy in cryptogenic hyperzincemia: a case report. Acta Biomed. 2021 Feb 5;92(1):e2021054. doi: 10.23750/abm.v92i1.9730. PMID: 33682842; PMCID: PMC7975935.
4. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006 Oct;81(10):1371-84. doi: 10.4065/81.10.1371. PMID: 17036563.
5. Kumar N, Crum B, Petersen RC, Vernino SA, Ahlskog JE. Copper deficiency myelopathy. Arch Neurol. 2004 May;61(5):762-6. doi: 10.1001/archneur.61.5.762. PMID: 15148156.
6. King D, Siau K, Senthil L, Kane KF, Cooper SC. Copper Deficiency Myelopathy After Upper Gastrointestinal Surgery. Nutr Clin Pract. 2018 Aug;33(4):515-519. doi: 10.1177/0884533617713955. Epub 2017 Dec 14. PMID: 28659010.
7. Gwathmey KG, Grogan J. Nutritional neuropathies. Muscle Nerve. 2020 Jul;62(1):13-29. doi: 10.1002/mus.26783. Epub 2019 Dec 26. PMID: 31837157.
8. Jolobe OM. Copper deficiency and myelopathy after bariatric surgery. J R Coll Physicians Edinb. 2018 Mar;48(1):92. doi: 10.4997/JRCPE.2018.120. PMID: 29741536.
9. Bookatz A, Osgood J, Celedon M, Holtz M, Young N, Ostermayer D, Donaldson R. Weakness. Donalds RI, ed. WikEM, The Global Emergency Medicine Wiki. Los Angeles, CA: OpenEM Foundation; 14 May 2022.
10. Sochet, Anthony & Jones, Amber & Riggs, Carl & Weibley, Richard. (2013). A 3-Year-Old Boy with Severe Anemia and Neutropenia. Pediatric annals. 42. 15-7. 10.3928/00904481-20121221-06.