Acute-Onset Weakness, Deafness, and Confusion: A Case of Multisystem Thiamine Deficiency

A 58-year-old woman with a history of squamous cell carcinoma of the palate resected 1 year previously, diabetes with peripheral neuropathy, and cocaine and alcohol use disorder presented with subacute, progressively worsening leg weakness, acute onset of inability to walk, bilateral hearing loss, and confusion. Several months before admission, she had developed progressive difficulty with ambulation and paresthesias in the bilateral arms and legs. She began tripping secondary to bilateral foot drop. One week before admission, she acutely and concurrently developed an inability to lift herself off of the floor, confusion (as reported by her significant other), and bilateral hearing loss. Her family reported that she uses alcohol heavily, and, since her palate resection, has had poor food intake.

Mental status examination was notable for impaired short- and long-term memory, recalling 0/3 words after 5 minutes, and the patient noting that she was just with her brother, who had died the previous year. Orientation, attention, and language were normal. There were bilateral abduction deficits with gaze-evoked horizontal and vertical nystagmus. There was severe bilateral hearing loss. There was distal greater than proximal symmetric weakness (1 to 2/5 distally, 3/5 at the hips) in the legs and mild diffuse weakness (4/5) in the arms. She had decreased light touch and vibration sensation on the bilateral lower extremities, as well as severe proprioceptive deficits at bilateral fingers and toes. Arm reflexes were 1+ and symmetric; leg reflexes were absent. Finger-nose-finger demonstrated past pointing and overshooting.

Diagnostic Process

A CT of the head demonstrated mild diffuse global brain atrophy for age. An MRI of the brain was marked by significant motion degradation, but there was no clear abnormality visualized. An MRI cervical and thoracic spine was unremarkable. An audiogram demonstrated severe bilateral sensorineural hearing loss (Figure 1). Nerve conduction studies and EMG demonstrated moderate-to-severe sensory greater than motor axonal polyneuropathy (Table 1). Laboratory studies for common causes of axonal polyneuropathy, including serum protein electrophoresis/urine protein electrophoresis and vitamin B12 level, were normal. Additional laboratory studies, including hepatitis C, rapid plasma reagin, cryoglobulins, vitamin E, and copper, were normal. The whole blood thiamine level was low at 50 nmol/L (normal >70 nmol/L). A whole blood thiamine level obtained 1 y before admission indicated 113 nmol/L.

Case Resolution

The acute onset of ataxia, nystagmus, and confusion in a person with decreased oral intake is highly suggestive of Wernicke encephalopathy from thiamine deficiency. The patient was treated with empiric thiamine repletion (500 mg IV 3 times daily for 5 days, followed by 250 mg IV daily for 3 days, followed by 100 mg oral thiamine daily). Her low whole blood thiamine level supported the diagnosis of Wernicke encephalopathy from thiamine deficiency, although it is important to remember that normal blood thiamine level may not accurately reflect intracerebral thiamine deficiency. Therefore, diagnosis and treatment should not be delayed if clinical suspicion is sufficiently high, even if the blood thiamine level is normal.¹ Our patient’s distal symmetric sensory-predominant axonal neuropathy is likely secondary to a combination of thiamine deficiency (dry beriberi) and neurotoxicity from chronic alcohol use. Given the acute-onset nature of the sensorineural hearing loss, concurrent with the acute onset of ataxia and confusion, we believed that the sensorineural hearing loss was also secondary to thiamine deficiency.

After thiamine repletion, the patient’s hearing loss almost completely resolved. Her extraocular movement abnormalities normalized and her weakness improved. Upon discharge, about 1 week after thiamine replacement, the patient continued to be confused and have distal greater than proximal sensory loss.

Discussion

Thiamine (vitamin B1) is an important cofactor required for the biochemical processes associated with the metabolism of lipids, glucose, amino acids, and neurotransmitters. Thiamine deficiency leads to multiple metabolic derangements, including cellular energy deficit, focal acidosis, increased glutamate release, and, eventually, neuronal apoptosis.² Low intracellular thiamine impairs oxidative respiration, as it is an integral cofactor in the Krebs cycle, which, in neurons, results in in neuronal depolarization.³ As a consequence, glutamate is released from cells, leading to excitotoxicity. Gross pathologic changes can be seen in areas most affected by thiamine deficiency, including the thalamus, mammillary bodies, and periaqueductal gray matter. The most common changes include petechial hemorrhages, hypertrophy of capillary endothelial cells, and neuronophagia.⁴ There is also Purkinje cells loss and shrinkage of the granule cell layer in the cerebellum, especially in the anterior superior vermis, which is thought to correlate with the ataxia seen clinically.⁴ These gross changes often can be seen on neuroimaging, with the most common imaging abnormalities in Wernicke encephalopathy being hyperintensities in the anterior nuclei of the thalamus, periaqueductal gray, and mammillary bodies.⁵

Individuals typically require 1 to 2 g of thiamine daily, which increases with chronic alcohol consumption and other malabsorptive diseases.² Chronic alcohol consumption leads to damage of the intestinal mucosa, disrupting thiamine absorption.² Hepatic disease interferes with thiamine storage and alters its transport, furthering the deleterious effects of alcohol^.2 People with chronic gastric malabsorption disorders (eg, bariatric surgery, hyperemesis gravidarum) require larger quantities of thiamine to absorb the daily requirement, and thus are at a higher risk for deficiency.^6,7 Patients with anorexia, prolonged fasting, systemic malignancy, and dialysis also are at increased risk of deficiency.

The classic findings of thiamine deficiency were first described by Carl Wernicke in the late 19th century. Wernicke encephalopathy is characterized by the triad of confusion, ophthalmoplegia, and gait ataxia. However, these symptoms rarely present together, and other symptoms can be present, including vestibular dysfunction, peripheral neuropathy, and stupor.⁶ In autopsy-confirmed cases of Wernicke encephalopathy, only 16.5% of patients presented with the complete triad of confusion, ophthalmoplegia, and gait ataxia; 37% of patients had only 1 of the 3 symptoms. Findings on neuroimaging are inconsistent—only 70% of people have imaging abnormalities in the thalamus, 60% in the periaqueductal gray, and 50% in the mammillary bodies.^5,8 One study reported the sensitivity of neuroimaging in diagnosis of Wernicke encephalopathy at 53%. Whereas a majority of individuals have imaging abnormalities, the absence of these should not preclude the diagnosis and clinicians should have an extremely low threshold to treat empirically with thiamine.^9,10 The confusion in Wernicke encephalopathy classically is described as both anterograde and retrograde amnesia with preserved long-term memory.⁶ The memory deficits correlate to the pathologic findings found in the Papez circuit. Despite appropriate treatment with thiamine repletion, 75% of patients will be left with permanent short-term memory loss, and 25% will require long-term institutionalization.² Ophthalmoplegia commonly presents as bilateral lateral recti palsies but may involve other extraocular muscles. Horizontal nystagmus on far lateral gaze is common, but vertical nystagmus also can be seen. Ocular findings correlate to the pathologic findings in the periventricular area of the third and fourth ventricle.¹¹ Ataxia is often truncal, a sum of damage to the cerebellum, peripheral nervous system, and vestibular system.

Peripheral neuropathy is a common manifestation of thiamine deficiency. Thiamine deficiency typically leads to an acute or subacute distal symmetric sensorimotor axonal polyneuropathy. At a clinical level, the person typically notices weakness and dysesthesias in the distal extremities.⁴ On a pathophysiologic level, beriberi is secondary to axonal degeneration with preservation of small myelinated and unmyelinated axons.

Thiamine deficiency also has been attributed to several cases of bilateral hearing loss.⁷ Localization of the lesion leading to hearing loss appears to vary between the medial geniculate nuclei of the thalamus or peripheral cochlear nerves. Mice with the thiamine transporter knocked out all developed an auditory neuropathy.¹² Furthermore, thiamine-responsive megaloblastic anemia syndrome, an autosomal recessive mutation in the high-affinity thiamine transporter protein (THTR-1), invariably is characterized by sensorineural hearing loss.¹³ As such, thiamine is important to the proper functioning of the auditory system.

Conclusion

Thiamine deficiency classically causes severe neurologic deficits such as confusion, ophthalmoplegia, and ataxia. Fewer than 20% of patients will have all three of those symptoms. Less common manifestations include sensorineural hearing loss or a distal peripheral neuropathy. We describe a case of thiamine deficiency leading to all of the common and less common manifestations. The patient’s hearing loss markedly improved with thiamine repletion, as did her ophthalmoplegia.