Hypocupraemia-induced anaemia, sensory ataxia and cognitive impairment secondary to zinc-containing dental adhesive

Abstract

A 67-year-old man presented with 5 months of worsening memory impairment and sensory gait ataxia on the background of symptomatic anaemia. He experienced falls, agitation and became socially withdrawn over 3 weeks, resulting in hospital admission. On examination, he had sensory gait ataxia consistent with a dorsal column syndrome. He scored 13/30 on the Montreal Cognitive Assessment. Serum analysis showed normocytic anaemia and leucopenia, severe hypocupraemia, reduced caeruloplasmin and normal zinc levels. Overuse of zinc-containing denture cream was the cause of excess zinc ingestion and resultant copper deficiency, leading to blood dyscrasia and myelopathy. The cream was withdrawn and intravenous and then oral copper supplementation was implemented. Direct questions with regard to excess zinc in the diet and serological testing of copper and zinc should be considered in any patient with a dorsal column syndrome, particularly with concurrent anaemia. Copper deficiency may also have a role in exacerbating pre-existing cognitive impairment.

Background

The link between hypocupraemia and haematological abnormalities, such as anaemia, and neurological disorders, such as sensory ataxia and myelopathy, is well established.^{1 2} A clear relationship between copper levels and cognitive function has never been described, although, both in excess and deficiency, copper has been linked to exacerbating cognitive impairment and dementia.^{3 4} Similarly, zinc, in either excess or deficiency, has been reported to be linked to cognitive function, Alzheimer’s disease (AD) and multiple sclerosis.^{3 5} Our patient had symptoms and signs consistent with copper deficiency including anaemia and leucopenia and a dorsal-column syndrome, but also profound cognitive impairment. Copper deficiency has been reported in states of malabsorption, post-gastrointestinal surgery or in the context of coeliac disease,^{1 2} and also in individuals consuming excess zinc.^{6 7} The use of dental fixative cream in the UK is common, with zinc-containing and zinc-free formulations available. Case reports describe a copper-deficiency myelopathy from excess use of dental fixative containing zinc^6–9; however, cognitive impairment has not been reported in this scenario. Early recognition is paramount in managing copper deficiency as the neurological sequelae of hypocupraemia may be permanent. Patients and doctors remain poorly aware of the potential of excess zinc or low copper to cause severe neurological disability and this case highlights that prompt recognition and testing is paramount.

Case presentation

A 67-year-old man presented with a 5-month history of progressive gait ataxia and decreased sensation of the lower limbs, numbness of the fingertips, decreased coordination in all four limbs and multiple falls. The patient’s next of kin described 5 months of progressive forgetfulness, followed by significant social withdrawal. In the 3 weeks prior to admission, there was noticeable deterioration, characterised by marked incoordination of the upper and lower limbs, resulting in falls and a tendency to drop objects.

The patient has a medical history of chronic obstructive pulmonary disease and Barrett’s oesophagus. Three months prior to the index admission, he was found to have symptomatic anaemia, causing dyspnoea, thought (initially) to be due to iron deficiency. Regular medications included ferrous fumarate and omeprazole.

Importantly, the patient had been using a generic brand of fixative cream, which did not contain zinc, but switched to a zinc-containing denture adhesive in the 7 months prior to admission, due to cost. After the switch, his usage increased significantly, to the extent of applying at least one 70 g tube per week. This amount is significantly in excess of the recommended usage, which states that a 70 g tube should last a minimum of 8 weeks.¹⁰

He was a current smoker with a 50 pack-year history and was consuming over 50–60 units of alcohol per week chronically, which was reduced in the months prior to admission. He had a history of previous, but not current, intravenous drug use. The patient reported low mood for approximately 2 years and had been previously treated for depression by his general practitioner. He had no significant family history.

The patient was fully mobile and socially active prior to developing gait ataxia; however, he had deteriorated to being totally housebound over the course of 4–5 months prior to admission. This had contributed to worsening mental health. His physical disabilities meant he was unable to purchase alcohol and so his alcohol consumption gradually decreased.

Examination revealed confusion and agitation, with an initial Montreal Cognitive Assessment (MoCA) score of 13/30. The patient was unable to mobilise unaided. An unsteady, broad-based gait with Romberg’s sign positive was noted, but no muscle wasting, fasciculation or tremor. Cranial nerve examination was normal. Limb examination showed normal tone and power, with no pronator drift. Reflexes were present, and symmetrical, apart from absent supinator and ankle reflexes; plantar reflexes were flexor. There was mild incoordination at heel-shin testing (out of keeping with the severe ataxia). There was decreased vibration sense to the costal margins, and decreased joint position sense to the left first metacarpophalangeal, right knee and the left ankle joints, respectively.

After 6 years of using a generic zinc-free dental adhesive with no symptoms, the switch to zinc-containing Fixodent coincided with the onset and progression of neurological and haematological abnormalities.

After copper replacement and 4 months of inpatient neurorehabilitation, there was significant improvement in cognitive scores but concerns remain of an underlying neurodegenerative or alcohol-related cognitive syndrome, while the gait ataxia improved to mobilising with a four-wheeler frame.

Investigation

Serum blood analysis

Three months prior to admission, the patient presented with dyspnoea. Routine serum analysis (see table 1) identified normocytic anaemia (haemoglobin 67 g/L, mean corpuscular volume (MCV) 86.5 fL), leucopenia (white cell count (WCC) of 2.7×10⁹/L), neutropenia (0.7×10⁹/L) and lymphopenia (0.7×10⁹/L). Additionally, packed cell volume (PCV) and mean corpuscular haemoglobin (MCH) were both low (0.217 L/L and 26.7 pg, respectively). Platelet count was normal (280×10⁹/L). Blood film analysis showed anisocytosis. Vitamin B12 and folate were normal at 199 ng/L and 3 ng/mL, respectively. Iron studies showed low iron at 2 µmol/L and reduced transferrin saturation at 4%. Transferrin and ferritin levels were normal at 2.47 g/L and 34 µg/L, respectively.

Table 1.

Blood results 3 months prior, on admission and post-copper repletion

Blood	Normal range	3 months prior	Admission	Post-copper repletion
Hb (g/L)	130–170	67	93	139
WCC (×109/L)	4–11	2.7	2.6	9.9
MCV (L/L)	80–100	86.5	90.6	83.0
Platelets (×109/L)	150–400	280	265	350
B12 (ng/L)	>160	199	175	209
Folate (mg/mL)	2.9–20.6	3.0	4.5	22.7
Iron (μmol/mL)	8–32.6	2.0	3	Not available
Ferritin (μg/L)	23.9–336	34	88	24
CRP (mg/L)	0–7.5	Not available	61	12
Copper (μmol/L)	12–26	Not available	1.2	17
Zinc (μmol/L)	11–24	Not available	16.1	12.2

CRP, C-Reactive Protein; Hb, haemoglobin; MCV, Mean Corpuscular Haemoglobin; WCC, White Cell Count.

On admission, having received oral iron replacement, serum blood analysis showed normocytic anaemia (haemoglobin 93 g/L, MCV 90.6 fL), leucopenia (2.6×10⁹/L) with platelets 265×10⁹/L and CRP of 61 mg/L.

Serum copper and caeruloplasmin were reduced at 1.2 μmol/L (10–22 μmol/L) and <60 (150–320), respectively. Serum zinc, vitamin B12 and folate levels were normal at 16.1 μmol/L, 175 ng/L and 4.5 ng/mL, respectively. Glucose and HbA1c levels were normal. Coeliac, HIV, hepatitis C and syphilis serology were all negative.

Imaging

MRI of the head excluded an intracranial lesion but showed global cerebral atrophy greater than expected for his age. MRI of the whole spine showed degenerative disc disease affecting the cervical spine, but no evidence of cord compression. There was possible intrinsic cervical cord increased signal.

Hexamethylpropyleneamineoxime - Single photon emission computed tomography (HMPAO-SPECT) scan analysis performed 4 months after admission revealed mid-cingulate and left temporal lobe perfusion deficits. With threshold reduction, the changes extended over the superior aspect of the left angular gyrus. The precuneus was normal at standard reporting thresholds but at reduced threshold left precuneus deficit was seen. While this is mildly abnormal, it did not reach diagnostic changes for any neurodegenerative disease.

Nerve conduction studies

Nerve conduction studies showed normal sensory responses from the hands and feet and normal motor studies and F-waves from the limbs. Central motor conduction time to the right foot was prolonged, but was normal to the right hand, consistent with dysfunction of the spinal pathway. No large fibre peripheral polyneuropathy or ganglionopathy was found.

Cognitive tests

MoCA on admission was 13/30 (Cu 1.2 μmol/L); after 2 months, it was 19/30 (Cu 6.2 μmol/L); and after 4 months, it was 22/30 (Cu 16.9 μmol/L).

Differential diagnosis

A progressive sensory ataxia affecting proprioception and joint-position sensory modalities localises the lesion to the dorsal column gracile and cuneate fasciculi. This is supported by nerve conduction studies showing grossly normal peripheral nerve function with evidence of delay at the level of the cord, and also by the MRI changes showing likely signal change in the cervical cord.

A compressive cervical myelopathy causing the sensory ataxia was excluded.

Vitamin B12 deficiency is a common cause of dorsal column sensory ataxia¹¹ but was ruled out by serology. Infective causes including syphilis, HIV and hepatitis C and were additionally excluded.¹¹

Copper deficiency is a recognised cause of myelopathy and was found in this case.^{2 11} Risk factors for copper deficiency include previous upper gastrointestinal surgery,^{2 11} malabsorption and excess zinc.^{2 12} Chronic ingestion of excess zinc-containing dental fixative makes this the most likely cause of myelopathy, and normal serum zinc levels are compatible with this. Haematological abnormalities are known to occur in copper deficiency and are present in this case, supporting the diagnosis.²

MRI changes showing cerebral and cerebellar atrophy suggest a separate and chronic pathology. This can be seen in chronic alcohol use, which was present in our case, or another underlying, pre-existing neurodegenerative syndrome. The HMPAO-SPECT scan could represent the early hypoperfusion deficits that can be seen in early AD. However, the history of a sharp decline in cognition in the 5 months prior to admission suggests the presence of an acute-on-chronic aetiology.

The patient presented with a raised C-reactive protein (CRP), suggesting the presence of an infection. However, the onset of cognitive decline coincides with the onset of sensory ataxia, suggesting shared causality. On admission, the patient had no chest or urinary symptoms, and urinalysis and chest radiography were normal, and therefore, the decline in cognitive function could not be attributed to an infectious cause. Brain imaging showed no evidence of encephalitis or other acute cause. Additionally, a delirium screen showed normal results for Erythrocyte Sedimentation Rate (ESR), B12, folate and Thyroid Function Tests (TFT).

Despite a history of chronic alcohol abuse, there was no history of a recent increase in alcohol or illicit drug use. While a toxicology screen was not performed, the patient’s relatives reported a gradual decrease in drinking over 4–5 months prior to admission, due to the patient’s worsening neurological function, which physically prevented him from leaving the house to purchase alcohol. Additionally, the patient and his family reported that he had abstained from illicit substances for several years. Therefore, in the absence of other clear causes of accelerated cognitive impairment and delirium, we postulate that copper deficiency could have exacerbated underlying mild cognitive impairment (possibly due to chronic alcohol excess or a neurodegenerative condition).

To conclude, the diagnosis prompting presentation in our case was sensory ataxic myelopathy due to copper deficiency on a background of mild cognitive impairment from chronic alcohol use. We propose that the derangement of copper may not cause recognisable cognitive impairment or delirium in a person with good cognitive reserve, although it may have precipitated a delirium in our case.

Treatment

The patient was advised to stop applying zinc-containing dental fixative cream.

He was administered 160 µmol of copper distributed between three intravenous infusions (IVIs) throughout his admission.

Intravenous copper replacement and cessation of Fixodent application led to normalisation of serum copper levels (see figure 1).

Figure 1.

The relationship between Montreal Cognitive Assessment (MoCA) scores and serum copper levels.

Additionally, he was prescribed copper chelate 8 mg/day for 1 week, 6 mg/day for 1 week and 4 mg/day for 1 week. Once copper was replete, iron was corrected by IVI. The patient was placed on oral copper chelate 2 mg/day and was discharged to a rehabilitation centre.

Outcome and follow-up

After discharge, the patient was admitted to a specialist neurorehabilitation centre for 4 months, where he underwent physiotherapy. The patient attended a follow-up appointment 3 months after discharge, joined by a designated carer.

Cognition

During his hospital admission, the patient’s mental state improved, demonstrated by an improved MoCA score; 13 when hypocupraemic and 22/30 3 months later (see figure 1). The patient’s cognition was followed-up for 16 months and his MoCA remained stable at 9 and 16 months (20/30 both times). This was reinforced by reports from the patient’s close friend who noted a dramatic improvement in his cognitive state, and by the patient himself, who reported feeling a lot more aware and comfortable with his own mental state. The patient’s carer stated that there were no obvious memory concerns in day-to-day life. A lumbar puncture to assess for CSF AD biomarkers was declined by the patient and so was longitudinal functional imaging.

Neurological symptoms

There was mild improvement in mobility, as the patient was able to walk with a Zimmer frame, only requiring a wheelchair for longer distances. Subjectively, the patient reports that his mobility is improving.

At follow-up appointment, on examination the patient found it very difficult to stand from his wheelchair and was unsteady even with the support of two people. Examining him on the chair, he had full power throughout. He had present upper limb reflexes and knee jerks but absent ankle jerks. Plantar responses were withdrawing. He had normal pinprick sensation, reduced vibration sense to the knees and normal in the upper limbs, reduced joint position sense to the left interphalangeal joint of the left hand, but normal in both feet. Compared with the original inpatient examination, he showed improvement, but remained very unsteady and functionally significantly impaired.

Discussion

Ingestion of zinc-containing dental fixatives, in excess of manufactures’ guidelines, has been linked to reports of hypocupraemia for some time.6 7 9 13 The mechanism by which this occurs involves the intestinal protein metallothionein, which preferentially binds copper in the gut.¹⁴ As dietary zinc levels rise, metallothionein synthesis increases, resulting in ingested copper not being absorbed but instead excreted in the faeces.¹⁴

This case report reinforces what is already stated in the literature, that hypocupraemia, secondary to high zinc ingestion, can cause minimally reversible dorsal column sensory ataxia in a manner that is clinically indistinguishable from vitamin B12 deficiency.6 7 9 13 Our patient’s mild improvement in his gait reflects what is known about outcomes in hypocupraemia-induced myelopathy.⁹

Imaging has shown that our patient had evidence of global cerebral atrophy and temporal lobe cortical perfusion deficits, suggesting the presence of a pre-existing incipient neurodegenerative process; we are not able to define this further. Possibilities include previous chronic alcohol excess or mild AD.

Interestingly, chronic cognitive decline has been associated with serum levels of copper and zinc, although the evidence is conflicting.¹⁵ Several papers have found an association between copper deficiency and the progression of AD.^{16 17} This is thought to be due to overexpression of amyloid protein due to hypocupraemia.¹⁷ Conversely, it has been implicated that copper ion toxicity has a role in AD.¹⁸ It has been shown that Cu2+ ions bind to beta-amyloid peptides with high affinity and increase the proportions of beta-sheet and alpha-helix structures in amyloid peptides, which can be responsible for beta-amyloid aggregation and neurotoxicity.¹⁸ Additionally, elevated serum zinc has been associated with the development of AD.¹⁹

We present a case of dorsal column sensory ataxia, with accelerated cognitive decline, induced by hypocupraemia. The cognitive impairment improved following repletion of serum copper and withdrawal of zinc-containing dental adhesive. The fact that the patient’s MoCA score improved with repletion of copper but never reached normal limits could be consistent with our hypothesis that this took place on a background of chronic neurodegenerative change.

Syndromes of gait sensory ataxia associated with cognitive decline have been seen in vitamin B12 deficiency^{11 20} and neurosyphilis.²¹ This case report can be used as a learning point to consider hypocupraemia as a differential diagnosis in patients who present with a dorsal column sensory ataxia and cognitive impairment. Acute cognitive decline associated with infection and vitamin B12 deficiency is widely reported,²⁰ but was excluded here, in favour of copper deficiency.

Furthermore, a case such as this highlights the need for better labelling and awareness of the risks of excess zinc ingestion. This is especially true of the age demographic likely to be using dental adhesives—elderly, and potentially with some level of chronic cognitive dysfunction. This may have contributed to excess usage in our case, postulated to have been driven by episodic amnesia due to incipient AD or chronic alcohol misuse.

On admission, the patient’s Hb was 93 g/L and WCC was 2.6×10⁹/L. This is consistent with what is known in the literature regarding copper deficiency-associated haematological abnormalities²²—a myelodysplastic pattern. We suggest that when a patient presents with neurological dysfunction coupled with myelodysplasia as present in this case, that this should trigger investigations for copper deficiency. Earlier recognition and diagnosis may prevent further neurological deterioration which, once severe, may only be partially reversible.

Limitations

We acknowledge that vitamin E deficiency can also present with ataxia and peripheral neuropathy and was not measured in this case.

Unfortunately, methylmalonic acid level is not available to us at our hospital and homocysteine was not sent to ensure that the underlying cause was not functional B12 deficiency. However, we feel the very low copper level and the improvement with copper replacement is compelling evidence that this was caused by copper, not B12, deficiency.

Similarly, we considered whether B₁ deficiency from chronic alcohol use could account for the sensory ataxia and cognitive impairment, but B₁ levels are not able to be measured at our hospital and the most parsimonious explanation remains copper deficiency, as the latter would also explain the haematological dyscrasia which also improved with copper replacement.

Lack of a toxicology screen on admission may present with significant differentials, which, although unlikely given the patient’s history, cannot be ruled out.

CSF for AD biomarkers were offered to the patient but he declined this investigation.

Patient’s perspective.

To watch a loved one deteriorate from being fully fit and mobile to confused and housebound would be difficult to endure for any family member or friend.

We spoke to the patient’s daughter and a close friend of 40 years, who first noticed he was becoming confused 8–10 months prior to admission. They stated he would forget the names of his next of kin and call people by their father’s or sister’s names instead of their own. He also developed episodic memory loss, for example he would call friends to come to his house, and upon arrival would ask them why they had come.

The condition had a profound effect on his quality of life. He would previously go out with his friends socially every week, an activity which had totally subsided in the weeks prior to admission. He became isolated and house bound, with untidy surroundings. His previously diagnosed low mood was exacerbated by this. He gradually went from drinking 5–6 pints of beer a night, 6 months prior to admission, to nothing in the weeks prior, due to physically being unable to procure alcohol. Following his increasingly frequent falls, his daughter decided to take him to our hospital’s Emergency Department.

Following diagnosis and treatment of his condition, our patient spent several weeks at a specialist neuro-rehabilitation centre. There, he re-learned key skills in order to maintain a healthy, independent lifestyle.

Learning points.

• Hypocupraemia may lead to reversible cognitive decline and a dorsal column-like syndrome.

• Due to the minimally reversible nature of hypocupraemia-induced sensory ataxia and its potential impact on cognition, early recognition, diagnosis and repletion is paramount for better outcomes.

• Copper levels should be routinely checked when a patient presents with dorsal column syndrome-like symptoms and/or haematological myelodysplasia.

Ethics statements

Patient consent for publication

Next of kin consent obtained.