Treatment response in osmotic demyelination syndrome presenting as severe parkinsonism, ptosis and gaze palsy

Abstract

Osmotic demyelination syndrome commonly affects the pons and infrequently involves the extrapontine region. We report a patient with severe hyponatraemia who developed osmotic demyelination syndrome as a consequence of rapid sodium correction. The condition manifested as acute severe parkinsonism, bilateral ptosis and gaze impairment. MRI revealed typical features of central pontine and extrapontine myelinolysis. The patient improved gradually after treatment with a combination of levodopa, intravenous immunoglobulin and dexamethasone. However, it is important to emphasise that the improvement of neurological symptoms is not necessarily causal with these experimental therapies.

Background

Osmotic demyelination syndrome (ODS) can give rise to serious neurological complications, primarily because of the involvement of the brainstem. The common features are quadriplegia, dysarthria, dysphagia and in severe cases, locked-in syndrome. Acute severe parkinsonism in association with bilateral ptosis and gaze impairment is rarely reported. In the past, severe ODS was associated with unfavourable neurological prognoses in 25%–31% of cases.^{1 2} Treatment is usually supportive because the disease is principally attributed to osmotic imbalance and is non-inflammatory in nature. However, in recent case reports, intravenous immunoglobulin has been found to be beneficial. In our case, a combination of immunoglobulin, dexamethasone and levodopa was administered during the early stage of illness, and possibly helped to improve the neurological outcome.

Case presentation

A 59-year-old man presented with a 3-week history of constipation. He took laxatives regularly, which temporarily relieved symptoms. The results were one to three bowel movements daily, which each consisted of small amounts of soft stool. However, he had a 2-week history of increasing lethargy, with poor appetite and intermittent vomiting. Despite this, treatment with laxatives continued through the second week of illness. There was no rectal bleeding, abdominal pain or distension. A few days prior to presentation, the patient’s wife noticed that he appeared confused and spoke incoherently. He had no history of fever, headache, seizure or any focal neurological symptoms. There was no loss of weight or other symptoms to suggest malignancy.

His history included hypertension and ischaemic heart disease since 5 years prior. His current medications included aspirin, clopidogrel, ramipril, bisoprolol, atorvastatin and pantoprazole. He had no history of treatment with diuretics for hypertension. He did not consume alcohol and he was a non-smoker.

On examination in the emergency room, he was drowsy but was able to obey commands. He had dry skin and a coated tongue. His vital signs at the time were a blood pressure of 130/80 mm Hg, pulse rate of 90 bpm and temperature of 37°C. His capillary blood sugar was 8.0 mmol/L. No meningism or abnormal focal neurological signs were noted. The abdomen was soft and non-tender with no organomegaly apparent. Bowel sounds were present and normal. Other systems examined were also normal.

Investigations

Initial blood analyses revealed severe hyponatraemia with serum sodium of 100 mmol/L. Serum and urine osmolality were 222 mOsm/kg and 427 mOsm/kg, respectively. Urine sodium was 81 mmol/L. Both the urinary osmolality test and the urine sodium test were performed while the patient received fluid therapy. Other electrolytes were normal including, serum potassium, urea, creatinine, calcium and magnesium. Serum cortisol and thyroid function tests were also normal. A complete blood count revealed a white blood count of 11.2×10⁹/L, haemoglobin of 12.3 g/dL and platelet count of 224×10⁹/L. His C reactive protein test was negative and his erythrocyte sedimentation rate was 8 mm/hour. Unremarkable results were obtained from other tests, such as a liver function test, antinuclear antibody, HIV, hepatitis B, hepatitis C and venereal disease research laboratory (VDRL) screening test, blood and urine cultures, chest X-ray, urine full microscopic examinations, tumour markers such as carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), alpha fetoprotein and cancer antigen (CA) 19-9, tuberculin test, brain CT and abdominal ultrasound.

Differential diagnosis

The patient was diagnosed with altered consciousness secondary to a severe hypotonic type of hyponatraemia. The hyponatraemia was postulated to be the result of sodium loss via the gastrointestinal tract in combination with a poor intake of sodium. Another differential diagnosis that needed to be considered was syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Treatment

The patient was intravenously infused with 3% sodium chloride, while aiming for a sodium change of less than 10 mmol/L over 24 hours. Approximately 14 hours later, the serum sodium had risen to 108 mmol/L, after which the infusion was switched to 0.9% sodium chloride. However, within 24 hours of correction, the serum sodium increased further to 113 mmol/L (table 1).

Table 1.

Sodium levels related to the intravenous fluid regimen

	On admission within 6 hours	14 hours	24 hours	Day 2	Day 3	Day 4	Day 5	Day 6	Day 10
Serum sodium (mmol/L)	100	108	113	118	122	126	128	126	135
Total fluid intake per day (mL)	1700			2000	2800	1800	2500	3000	2800
Intravenous fluid regimen	3% NaCl	3% NaCl	0.9% NaCl
Conscious state	Drowsy			Conscious, alert			Drowsy		Conscious alert

Both ramipril and bisoprolol were withheld during this time in view of his impaired hydration status and normal blood pressure.

On the following day, the patient appeared to be more alert and improving. But, after 4 days, the delirium returned. His vitals were a blood pressure of 130/70 mm Hg, pulse rate of 88 bpm and temperature of 37°C. Neither hypoxaemia nor hypoglycaemia was observed. Although the patient was able to move all limbs, he did so with severe generalised rigidity, bradykinesia and tremor in all extremities. The tremor predominantly occurred at rest. Further examination revealed bilateral ptosis. His eye movements were impaired in both horizontal and vertical gazes, but his pupil size was bilaterally normal. Other cranial nerves were intact. Reflexes were normal with flexor plantar responses.

Because the patient’s neurological condition deteriorated, MRI was performed which revealed abnormalities (figures 1 and 2). An electroencephalogram showed mild diffuse slowing. The cerebrospinal fluid (CSF) was clear and acellular with normal protein and glucose levels. CSF tests were negative for culture, latex agglutination test for common bacteria, PCR for tuberculosis, Indian ink test, cryptococcal antigen and PCR for herpes simplex viruses.

Figure 1.

T2W Fluid attenuated inversion recovery (FLAIR) MRI image shows increased signal with involvement of bilateral thalamus and lentiform nucleus (red arrow).

Figure 2.

T2 FLAIR MRI image shows symmetrical hyperintensity in the central pons due to demyelination (red arrow).

The patient was diagnosed with ODS. Levodopa therapy was started using levodopa/benserazide at 100/25 mg, four times daily, in addition to anticholinergic, trihexyphenidyl 2 mg two times a day because the patient remained rigid and tremulous from severe parkinsonism. The improvement was small with the initial levodopa dosage, which was subsequently increased to 200/50 mg four times daily. The parkinsonism symptoms decreased, but his bilateral ptosis and gaze palsies remained nearly unchanged. His voice was slow, monotonous and could barely be heard. In view of these persistent symptoms and based on a review of case reports describing good response to immunotherapy, intravenous immunoglobulin (0.4 g/kg body weight) and dexamethasone were administered for 5 days. The 0.9% sodium chloride infusion was resumed at a slower rate. His serum sodium gradually rose and eventually normalised with treatment.

Outcome and follow-up

The patient subsequently underwent rehabilitation. The acute parkinsonism completely resolved after 3 weeks of treatment. His medications were safely tapered off without the reappearance symptoms. His ocular symptoms gradually improved during the follow-up period. At 3 months, he recovered significantly without neurological deficits and was independent in his daily living activities. His serum sodium remained within the normal range throughout his follow-up visits.

Discussion

ODS is an acute neurological emergency, characterised by myelinolysis and specifically involves the central pontine area. In 10% of cases, it leads to myelin destruction in extrapontine regions, such as the basal ganglia, thalamus, midbrain, cerebellum and cerebral hemisphere.^{3 4} It is thought to strike regions that are abundant in oligodendrocytes, which produce myelin. These cells are very susceptible to changes in serum osmolality.⁵

Rapid correction of severe hyponatraemia, beyond 10–12 mmol/L sodium replacement within a 24-hour period or exceeding 18 mmol/L in a 48-hour period, is thought to be the most common trigger of ODS.⁶ Either of these can lead to a crucial imbalance in the brain osmoles, notably during a chronic state of hyponatraemia, which can result in astrocyte death, disruption of the astrocyte–oligodendrocytes network, brain cell shrinkage, osmotic myelinolysis or secondary inflammation.^{5 7 8}

This patient had the hypotonic type of hyponatraemia. He appeared mildly dehydrated based on the dry skin and a coated tongue. The causes of his hyponatraemia were initially presumed to be the loss of water and sodium via the gastrointestinal tract and poor oral intake.⁹ However, the urine osmolality in severe hypovolaemic type is expected to be very high and the urine sodium can be low (<20 mmol/L), but neither were present in this patient.¹⁰ Nevertheless, the results must be interpreted cautiously because the tests were performed after fluid therapy and sodium replacement had begun.

Another possible cause is SIADH, which is compatible with the investigative results that indicate hypotonic hyponatraemia with inadequately diluted urine (osmolality exceeding 100 mOsm/kg) and urine sodium exceeding 20 mmol/L.¹⁰ However, with SIADH, the volume is expected to be normal. A subjective assessment of the volume status based on dry mucous membranes might not be accurate in some patients. In this case, no other common causes of SIADH were detected via the multitude of tests performed, such as infection, brain disease or malignancy. However, certain ongoing therapeutic drugs such as ramipril and pantoprazole have reportedly caused hyponatraemia of an unknown mechanism or possibly resulting from SIADH in certain patient subgroups, especially if taken in combination.^{11 12} To the contrary, the patient’s serum sodium level improved on fluid replacement rather than fluid restriction, which would not be expected in SIADH. Thus, the final exact cause of hyponatraemia in this case has not been proven, but is possibly the result of a combination of factors.

ODS can manifest 2–6 days after the correction of hyponatraemia.¹³ The calculation for sodium correction in this patient was aimed to impact serum sodium by less than 10 mmol/L over 24 hours, but that target was overshot. Notably, ODS can rarely occur during severe episodes of hypernatraemia.¹⁴ Common risk factors include malnutrition, excessive alcohol intake and the consumption of diuretics.

The clinical features of ODS are diverse and are determined by the affected region of the brain. Most frequently, pontine lesions occur at the basis pontis, resulting in symmetrical quadriplegia, dysarthria and dysphagia from myelinolysis of the corticospinal and corticobulbar tracts that run through the region. Locked-in syndrome can occur in severe cases. Another rare feature is altered consciousness resulting from involvement of the ascending reticular activating system.¹⁵

Extrapyramidal manifestations such as parkinsonism and dystonia have been reported, typically from involvement of the basal ganglia.^{15 16} This patient presented with acute parkinsonism and rare features of bilateral ptosis with both horizontal and vertical gazes palsy. The horizontal gaze palsy can be attributed to a lesion affecting the paramedian pontine reticular formation. Vertical gaze palsy and bilateral ptosis conventionally indicate a midbrain lesion. However, no MRI evidence of midbrain involvement could be found in this patient. These clinical features could be explained by lesions in other regions such as the putamen and thalamus (figure 1), due to involvement of the descending supranuclear pathway to the midbrain. Case reports described that lesions at these sites result in gaze palsy in all directions with bilateral ptosis.^{17 18} Other rarely reported extrapontine manifestations are tremor, ataxia, mutism and catatonia.¹⁵

The diagnosis of ODS in our patient is supported by the clinical course and MRI evidence. The differential diagnosis of acute parkinsonism includes stroke, encephalitis, haemorrhage and demyelination from inflammatory disease.

The MRI feature is very characteristic of ODS in that it has symmetrical hyperintensity in the central pons, in T2-weighted and FLAIR-MRI (figure 2).¹⁹ There were no features suggesting encephalitis as the patient was afebrile and had normal CSF.

The treatment is primarily supportive. Early detection and treatment result in better prognosis. Various modalities of immunotherapy have provided favourable outcomes in case reports, including immunoglobulin,^20–22 methylprednisolone^{23 24} and plasmapheresis.^{5 13 25} In this patient, immunoglobulin and dexamethasone were initiated early, in view of the severity of the disease and the partial improvement of parkinsonism with high-dose levodopa therapy during the acute stage. Furthermore, the eyes’ signs of bilateral ptosis and gaze palsies are less likely to respond to levodopa therapy alone.

The exact mechanism of immunotherapy is unknown, thus, it is regarded as an experimental therapy. A recent study has shown some axonal damage associated with inflammatory infiltrates in ODS.^{1 5} The initial osmotic event might trigger the release of myelinotoxic substances leading to secondary immune damage. Immunotherapy is postulated to either remove or reduce the effect of myelinotoxic substances. Atchaneeyasakul et al reviewed 10 case reports that showed neurological improvement in some patients with various predisposing factors for ODS, that were treated with intravenous immunoglobulin during the early course of the illness. Delayed treatment was associated with less satisfactory neurological improvement.²²

In ODS, several factors have been found to be associated with poor prognosis such as impaired consciousness, pontine lesions, severe hyponatraemia (serum sodium of 115 mmol/L or less) and hypokalaemia.^{1 26} Our patient had three of these poor prognostic features. Fortunately, he received early treatment within the first week of illness and recovered completely. Whether this outcome resulted from early immunotherapy remains hypothetical and requires further research.

For acute severe parkinsonism, levodopa therapy was instituted with some improvement of symptoms. Case reports that described ODS with acute parkinsonism in various associated disorders were shown to have moderate to good responses to dopamine replacement with levodopa.^{16 27 28} However, late-onset parkinsonism can occur after the acute stage and may be refractory to levodopa therapy.²⁹

Other methods reported for the treatment of ODS are thyrotropin-releasing hormone and reinduction of hyponatraemia.^{5 24 30} Relowering of sodium values has been shown to be safe in chronic hyponatraemia patients with the rate of sodium correction exceeding 8 mmol/L in a 24-hour period. Concomitant use of desmopressin and 5% dextrose for the reduction of serum sodium after an episode of overcorrection has been described.^{31 32}

Of the utmost importance is the prevention of ODS by avoiding the predisposing factors. Despite aiming for a correction of less than 10 mmol/L sodium, some patients will nonetheless develop ODS. Thus, it is recommended to lower the target when the patient is in a severe hyponatraemic state. A slower rate of sodium correction of no greater than 6–8 mmol/L over 24 hours is regarded as safe and can result in minimal complications.³³

Learning points.

• Osmotic demyelination syndrome (ODS) commonly occurs as a consequence of rapid correction of serum sodium in hyponatraemia patients.

• Acute severe parkinsonism in association with bilateral ptosis and gaze palsy are rarely observed in ODS.

• Despite good response to intravenous immunoglobulin and dexamethasone, these treatments remain an experimental therapy and require more evidence to support their use in ODS.

• Acute parkinsonism in ODS may respond to levodopa therapy.

• Slower titration is required during sodium correction to prevent ODS in severe hyponatraemia.