Locked-in Syndrome Secondary to Central Pontine Myelinolysis: A Case Report

ABSTRACT: Locked-in syndrome is a condition where the patient is aware and awake but cannot move or communicate due to complete paralysis of all voluntary muscles, except the eyes. It is often considered a disease of no hope, with no treatment and high mortality rates. This article seeks to identify the etiology, prognosis, and factors that contribute to the prognosis, with a focus on central pontine myelinolysis as a contributing cause.

Day 1-7:

A 41-year-old male presented to the emergency department with new onset of confusion and frequent falls.

History. He had been discharged from the same hospital 3 days prior following treatment for acute alcohol intoxication and acute chronic hyponatremia. The patient has history of ongoing alcohol abuse and admits to drinking 15 to 20 beers a day for at least 4 years. He has had at least 5 hospital admissions for mental status changes and profound hyponatremia (serum sodium ranging on admission from 92 meq/L to 119 meq/L). 

At the time of the patient’s hospital admission 1 week prior, his serum sodium was <100 meq/L. At that time, he was treated with 3% saline and had an interval increase in his serum sodium to 117 meq/L over approximately 24 hours. His hyponatremia and neurological status had improved to baseline and he was discharged from the hospital after approximately 72 hours. 

Because the dramatic increase in serum sodium level very likely contributed to the patient’s developed locked-in syndrome, we put the day of dramatic serum sodium change as day 1. At the time of hospital discharge at day 7, the patient had no focal neurological defects and his serum sodium was 132 meq/L. 

Day 11:

Three days later, the patient returned to the emergency department with the report of progressive difficulty in walking since his recent hospital discharge, as well as frequent falls and urinary incontinence. 

Physical examination. At the time of his presentation, he was agitated, but awake, alert, and able to provide a cogent history. The patient’s blood pressure was 140/90 mm Hg, heart rate of 105 beats per minute, respiratory rate of 26 breaths per minute, temperature of 99.3° F, and O2 saturation of 99% on room air. His neurological examination at the time only revealed mild lower extremity weakness. 

Laboratory testing. On admission, he had the following laboratory studies: white blood cells (WBC) 6.6/µl, hemoglobin 16.1 mg/dL, hematocrit 48.2%, and platelets numbered 276,000. Prothrombin time was 10.5 secs, INR was 0.9, and partial thromboplastin time was 30.2 secs. 

His urinalysis was normal except for the presence of trace ketones. Serum tests of renal function, liver function, electrolytes (including sodium which was 139 mEq/L), and cardiac enzymes were all normal. 

The patient had a serum ammonia level of 18 and negative blood alcohol level. A urine drug screen was positive for the presence of benzodiazepines. 

ECG and chest roentgenogram were normal. A noncontrast enhanced CT scan of the brain was completed and reportedly normal. 

Treatment. The patient was admitted to the hospital and initially treated with intravenous thiamine and benzodiazepines as needed for alcohol withdrawal symptoms. 

The patient then developed progressive profound generalized weakness with increased tone and hyperreflexes. He had evidence of pseudobulbar palsy with head and neck weakness, and the inability to speak or swallow. He appeared to have a horizontal gaze paralysis and was unable to follow commands. 

During that admission, a MRI study of the brain was performed which revealed hyperintense areas in the central pons (Figure)—which was felt to be consistent with central pontine myelinolysis (CPM). 

Due to swallowing dysfunction, a percutaneous endoscopic gastrostomy (PEG) tube was placed to facilitate nutritional support. On the day 14 of the hospital admission, the patient was discharged to a skilled nursing facility (SNF) for ongoing supportive care.

Figure. MRI of the brain revealed an area of restricted diffusion involving the central pontine fibers (A), corresponding to high signal on Flair/T2W (A’/A’’) with sparing the peripheral fibers consistent with osmotic demyelination. Three months later, the MRI showed low signal on diffusion (B), with corresponding high signal on Flair/T2W (B’/B’’) consistent with normal aging.

Day 23:

Upon transfer to the SNF, the patient was treated with enteral feedings via PEG tube, intensive physical therapy to prevent contractures and atrophy, frequent tracheobronchial suctioning, and prophylactic measures to prevent corneal abrasions and decubitus ulcers. The SNF staff was apprised that this patient was possibly in a “locked-in” state due to his CPM. Intensive effort was made to communicate with the patient via blinking or vertical eye movements, but true communication could not be achieved. 

During the patient’s SNF stay, he exhibited obvious cycles of sleep and wakefulness, and was occasionally noted to be crying. No spontaneous movements of the head or extremities were ever noted; but after about 2 weeks in the SNF, he was noted to move his eyes towards a verbal stimulus (when previously no horizontal eye movements could be appreciated). 

Day 43:

On day 21 of his stay at SNF, the patient had an episode of emesis and presumed aspiration. He shortly thereafter developed a fever to 102°F and was treated with antibiotics consisting of levafloxacin and ceftazidime. On the following day, when patient continued to be febrile and had increased respiratory distress, he was admitted to the hospital. 

Physical examination. Upon admission to the hospital, the patient’s blood pressure was 99/60 mm Hg, heart rate of 148 beats per minute, respiratory rate of 20 breaths per minute, temperature of 101.5°F, and O₂ satuation of 97% on 3 L/min nasal cannula. The patient was lethargic and diaphoretic. His mucus membranes were dry. His cardiac exam revealed a tachycardia with a regular rate. There were coarse rhonchi throughout his lung fields. His abdomen was soft and nontender. His neurological exam was essentially unchanged with a spastic paresis of his extremities, hyperreflexes, and the inability to speak. He was unable to cooperate with more detailed neurologic examination. 

Laboratory testing. His laboratory studies were as follows: WBC 19.1/µl with 19% band forms, hemoglobin 12.9 mg/dL, hematocrit 38.7%, pH of 7.43, PaCO₂ 33.8 mm Hg, and PO₂ 93 mm Hg on 6 L/min O₂ via nasal cannula. In addition, sodium was 144 meq/L, potasium was 3.9 meq/L, chloride was 114 mEq/L, and HCO₃ was 21 mEq/L. BUN was 48 and creatinine 0.93 mg/dL. 

A chest roentgenogram showed bilateral patchy infiltrates. The patient was admitted with a presumed diagnosis of aspiration pneumonitis and healthcare associated pneumonia. He was empirically treated with intravenous levofloxacin, clindamycin, and intravenous fluids. 

On the second day of this hospitalization, the patient suddenly began to speak fluently. He was discharged back to the SNF on hospital day 5. 

Day 49:

Upon returning to SNF, he began to show great improvement in his neurological condition. He continued to receive intensive physical, occupational, and speech therapy. His urinary catheter was discontinued without difficulty and his PEG was eventually removed. He was able to eat a normal diet at the time of SNF discharge. 

He was eventually able to ambulate independently, but continued to have mild bilateral foot drop. He remained mildly spastic and hyperreflexes, particularly in the lower extremities. 

Interestingly, the patient was able to relate details of his care, including conversations among caregivers in his room from the period of time when he appeared comatose, suggesting that he was truly in a “locked-in” state. 

Day 111:

A second MRI of the brain was done approximately 3 months after the patient’s initial study showed decreased high signal to baseline age-related level in the central pons consistent with resolution of CPM (Figure). The patient was eventually discharged home to the care of
his sister.

Defining Locked-In Syndrome

The term locked-in syndrome (LIS) was first introduced by Plum and Posner in 1966.¹ It is a catastrophic condition where a patient is aware and awake, but cannot move or communicate due to paralysis of nearly all voluntary muscles. Recently, the American Congress of Rehabilitation Medicine defined LIS as a neurologic impairment characterized by the presence of sustained eye opening, aphonia or severe hypophonia, quadriplegia or quadriparesis, preserved cognitive functioning, and a primary and elementary code of communication that uses vertical eye movements or blinking.²

There are 2 essential elements for the diagnosis of LIS: retained alertness and cognitive abilities, and paralysis of the limbs and oral structures, such that the individual cannot signal with the limbs or speak.^3,4 

To better understand the condition, a patient must first be diagnosed in 1 of 3 varities.^4,5 Note: The different areas of the ventral pontine neurons can vary the location and severity of the damage. 

• Classical is defined as ventral pontine damage that causes quadriplegia and the inability to speak or swallow, but the patient is totally conscious and able to use vertical eye movements and blinking to communicate. 

• Incomplete is similar to classical variety except that the patient has upper eyelid and vertical eye movement, as well as remnants of other voluntary motion (ie, finger twitch or tongue movement). 

• Total is when the patient is completely immobile and unable to communicate, such as our case. 

Etiology 

The most common etiology of LIS is vascular pathology, such as stroke, which accounts for 52% to 100% of case.^6-9 Stroke is likely the most common presentation that primary care physicians would encounter with LIS. However, other nonvascular causes of LIS include trauma, CPM, pontine abscess, brainstem tumors, meningitis, encephalitis, Reye’s syndrome, toxins, and heroin abuse.

Prognosis 

The majority of LIS patients have a poor prognosis. Mortality is indeed high in acute LIS—76% for vascular and 41% for nonvascular cases—with 87% of the deaths occurring in the first 4 months.¹⁰ The prognosis for survival and recovery was found to be better in the group of patients whose syndrome was nonvascular in origin versus a vascular etiology. Functional recovery, such as mobility and sphincter control, was generally good in those patients with a vascular etiology who survived beyond 4 months. There is evidence that younger patients have higher survival rates. 

Evidence suggests that once a patient has been medically stabilized for more than a year, 10-year survival is 83% and 20 year-survival is 40%.¹¹ Recent studies indicate that intensive and early rehabilitative care improves motor outcome and drops the mortality rate to 14% at 5 years.¹² 

Surprisingly, many LIS patients can return home. In 2008, the French Association for Locked-In Syndrome database indicated that, out of 158 patients, nearly 65% returned home, 8% remained in hospital setting, 11% in rehabilitation center, and 16% in nursing home.⁶ Furthermore, 58% of patients reported limited recovery, which included useful movements and monosyllabic speech, while 51% of the surveyed LIS patients used some kind of technological communication device. 

Of the 158 patients, 42 died. The reported causes of death were predominantly infections (40%) with pneumonia being the most common, primary brainstem stroke (25%), recurrent brainstem stroke (10%), and the patient’s refusal of artificial nutrition and hydration (10%).⁶ Other causes include cardiac arrest, gastrostomy surgery, heart failure, and hepatitis.

Reports on the prognosis of LIS in children find that 35% of pediatric LIS patients experienced some motor recovery, 26% had good recovery, 23% died, and 16% remained quadriplegic and anarthric.⁸

Outcome of the Case

In the abovementioned case, the history and physical examination suggested that our patient had central pontine myelinolysis. His MRI studies were consistent with a recently published report that showed a well-defined lesion in the pons of high T2-signal intensity.¹³ 

The head CT and magnetic resonance angiogram had ruled out other pathologies, such as the possibility that an ischemic or hemorrhagic stroke caused LIS in this patient. Therefore, we were confident with his CPM diagnosis. 

Our patient is young and has no underlying irreversible vascular disease. He did suffer from healthcare facility-associated pneumonia, which is treatable and reversible, and therefore gave him a better chance to recover from LIS. He received sufficient nutritional support and early aggressive rehabilitation. All of these considerations favor his positive outcome. 

What is Central Pontine Myelinolysis?

CPM is a noninflammatory, demyelinating condition, originally described in those with chronic alcoholism and in malnourished persons. The CPM primarily occurs with overly rapid correction of severe hyponatremia (plasma sodium concentration usually <110 mEq/L to 115 mEq/L) that has been present for more than 2 days, the time required for the cerebral adaptation to occur. However, some patients are at high risk and can develop this syndrome at higher baseline plasma sodium concentrations and lower rates of correction. 

Chronic hyponatremia is associated with the loss of osmolytes (ie, sodium, potassium, chloride, and organic osmolytes, such as myoinositol, glutamate, and glutamine) and water from brain cells, which provides protection against cerebral edema. However, the osmolytes cannot be quickly replaced as the brain volume shrinks in response to an elevation in the plasma sodium concentration. As a result, brain volume falls from a value that is initially somewhat above normal to 1 below normal with rapid correction of hyponatremia. 

Recent reports, however, indicate that the etiology of CPM can be multifactorial. It can happen in patients with hyperglycemia and hyperosmolar hypernatremia,¹⁴ or in patient with normal serum sodium concentration.¹⁵ Note: The fact that CPM can be seen in patients with different condition of serum sodium indicates the contribution of other trigger factors for the development of CPM. Therefore, special attention should be given to the group of patients at greater risk—including individuals with sudden changes in the plasma levels of serum sodium, liver transplantation, chronic alcoholics, and the malnourished. 

The precise incidence of CPM is not known, but the ability to diagnose it during life has been helped by modern neuroimaging, particularly with an MRI of the brainstem. Clinical manifestations of CPM include truncal and gait ataxia, pseudobulbar syndrome, and bilateral upgoing plantar responses. 

Severe CPM may cause LIS. A case of CPM has been reported in a 15-year-old female patient with severe anorexia nervosa who actually developed LIS, but eventually recovered completely, both clinically and radiologically.¹⁶

Treatment and Prognosis 

There is no proven effective therapy for CMP. Prevention is of primary importance, both by avoiding rapid sodium correction and by minimizing further elevations in the plasma sodium concentration when it does occur. 

After the onset of CPM, management should be supportive and directed towards minimizing morbidity and mortality. Based on the premise that myelinotoxic compounds and a speculative inflammatory process are contributing to the pathogenesis of CPM, patients have successfully been treated with plasmapheresis, intravenous immunoglobulins, and steroid administration.¹⁷ Although the results suggest possible benefit, they are difficult to interpret since some patients who undergo rapid correction of hyponatremia experience short-lived, spontaneously reversible episodes of neurological impairment. Additional studies with a larger number of patients are required to clarify the role of treatments, such as plasmapheresis, in the treatment of CPM. 

CPM has also been treated successfully with a daily thyroid-releasing hormone over 6 weeks. It remains unclear if these interventions provide benefits in alcohol-associated benign CPM. Recently, the introduction of a newer class of pharmacologic agents—the vasopressin receptor antagonists, known as Vaptans, which induce an excretion of increased amounts of water without altered sodium or potassium excretion—is of particular interest.¹⁸ More importantly, efforts should be made to help individuals stop their alcohol abuse and improve their nutritional status.

In the past, the prognosis of CPM was thought to be poor with a mortality rate of over 50%. With greater general awareness of the disorder and a better ability to diagnose it, the prognosis is improving. In some instances, complete recovery of CPM has been reported.¹⁹ 

However, there is only limited information of who will recover and what factor may affect recovery. Individuals who survive continue to have challenges with speech, walking, emotional ups and downs, and forgetfulness. 

LIS can be seen in severely affected CPM patients.¹⁵ In one review of 139 cases of LIS, 7 or 0.5% of cases were caused by CPM and 3 (or 43%) of those patients died.⁸ 

There is no guideline or consensus for the treatment of CPM-caused LIS. However, it is generally agreed upon that actively treating medical conditions reduces the risk of complications in the acute phase and should be followed with aggressive supportive therapy. 

Actively stabilizing medical conditions, aggressively preventing possible complications, and rehabilitation are essential to prevent death, as well as offer more time for the brain cells to adapt, recover, and reestablish the myeline sheath—which may lead to recovery.  ■

Daniel Yanfeng Lin, MD, PhD, is a hospitalist in Chambersburg Hospital, Chambersburg, PA, and a guest professor of clinical medicine at the Fujian Medical University, Fuzhou, China.

Jennifer L. Good, MD, is an associate director at the Altoona Family Medicine Residency Program at the University of Pittsburgh Medical Center in Altoona, PA, where she has been on the faculty for 18 years.

Donald M. Beckstead, MD, is a program director at the Altoona Family Medicine Residency Program at the University of Pittsburgh Medical Center in Altoona, PA, where he has been on the faculty for 29 years. 

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