Dysautonomia and hyponatraemia as harbingers of Guillain-Barre syndrome

Abstract

A 56-year-old woman with a medical history of hypertension presented to our hospital with back pain, abdominal pain, vomiting and elevated blood pressure. The laboratory parameters including evaluation for secondary hypertension were within normal ranges at the time of presentation. During her hospitalisation, fluctuations in her blood pressure and pulse were observed which were attributed to autonomic disturbances, the cause of which was unknown. On the seventh day after presentation to the hospital, the patient developed focal seizures and slurred speech which was believed to be secondary to hyponatraemia detected at that time. Hyponatraemia improved with hypertonic saline and she experienced no further seizures. On the eighth day of her admission, she developed acute flaccid paralysis of all her limbs and respiratory distress. We concluded this to be secondary to Guillain-Barre syndrome (GBS). She responded to plasmapheresis.

The presence of dysautonomia and hyponatraemia before the onset of paralysis makes this a rare presentation of GBS.

Background

Guillian-Barre syndrome (GBS) is an immune-mediated polyneuropathy that manifests in the form of an acute, ascending, areflexic, progressive and symmetrical paralysis. It was described by French neurologists for the first time in 1916, who observed the condition in two soldiers. Raised concentration of protein with normal cell counts were noted in the CSF.^{1 2} GBS includes four subtypes, such as acute inflammatory demyelinating neuropathy (AIDP), acute motor axonal neuropathy, acute motor and sensory axonal neuropathy and Miller-Fisher syndrome). The global annual incidence of GBS is 0.6–4 per 100 thousand individuals.³

GBS is not an uncommon condition in neurology. Dysautonomia and hyponatraemia are known to occur following the onset of motor weakness in this condition. However, it is rare for either of these to precede the motor weakness. In our patient, both of these features occurred before (8 days before and 1 day before, respectively) the paralysis manifested, thus making this a very rare presentation of a common neurological disease.

Case presentation

A 56 year-old woman, a known hypertensive (well controlled with telmisartan), with no history of diarrhoea, upper respiratory tract infection, high-risk sexual behaviour, surgery or recent immunisation, presented with 2 days of back pain, abdominal pain, vomiting and giddiness.

The back pain was dull, localised to the lower back and had no aggravating or relieving factors. The abdominal pain was dull in character and was generalised over the abdomen. Her blood pressure was 200/100 mm Hg with a pulse of 48/min at the time of presentation, with no other abnormalities on physical examination. Her baseline pulse rate used to be between 70 and 80/min. Her neurological examination, including testing for reflexes was normal. She did not give a medical history of missing her antihypertensive medications. She was not on any other medications. Her family history was negative for diabetes mellitus, cerebrovascular accidents, hypertension, thyroid diseases, renal diseases, epilepsy or any other neurological condition. Funduscopy showed changes suggestive of grade 1 hypertensive retinopathy and she was started on nitroglycerine infusion for treatment of hypertensive emergency. Her serum amylase and lipase were within normal limits (done in view of her abdominal pain, to rule out acute pancreatitis).

Workup for secondary causes of hypertension was normal (which included ultrasonography of the kidneys with renal doppler, serum metanephrines and serum vanillylmandelic acid levels, serum cortisol levels and tests for primary hyperaldosteronism)

During her hospitalisation, she had marked fluctuations in her blood pressure and heart rate, which were attributed to autonomic neuropathy, and had to be treated accordingly. Hypotension was managed with intravenous fluids whereas hypertension was managed with nitroglycerine. There was evidence of orthostatic hypotension, which also suggested cardiovascular autonomic disturbances. Her workup for diabetes mellitus was negative (which included fasting as well as post-prandial blood glucose, and glycosylated haemoglobin). No aetiology for her autonomic disturbances could be found at that time.

On the seventh day of her admission she became drowsy, had slurred speech and had right sided focal seizures with twitching of the right eye lid and right hand clonic movements. Her laboratory parameters revealed serum sodium of 107 mmol/L (from 138 mmol/L at the time of admission, and was not measured each day), potassium of 2.5 mmol/L, calcium of 9.1 mg/dL with urine osmolality being 577 mOsm/kg (normal range is 390–1000 mOsm/kg) and serum osmolality being 285 mOsm/kg (normal range is 390–1000 mOsm/kg). Her sodium was corrected with hypertonic saline, and was slowly raised to 124 mmol/L over 48 hours, after which her sensorium improved.

A day later, she started having tachycardia, tachypnea with laboured breathing with the use of the accessory muscles of respiration and paradoxical breathing, and oxygen saturation dropped as well, hence she had to be intubated (with no sedation being given). It was at this time, that it was noticed that she had bilateral facial weakness, areflexic flaccid paralysis of both her upper and lower limbs, with the plantar responses being flexor bilaterally. The respiratory distress was attributed to diaphragmatic paralysis. Her electrolytes were within normal limits at this time. MRI brain was normal. Cerebrospinal fluid (CSF) studies revealed albuminocytological dissociation with the protein being 223 mg/dL (normal range is 15–45 mg/dL), glucose of 96 mg/dL (normal range is 40–80 mg/dL), cells 4, adenosine deaminase 2, and negative for Ziehl-Neelsen staining. Electrophysiological study was compatible with GBS, showing generalised sensorimotor polyneuropathy with demyelinating features.

Differential diagnosis

One of the relevant differential diagnosis which was considered was hypokalaemic periodic paralysis, since the potassium level was low at the time of onset of the drowsiness. However, when the areflexic flaccid paralysis of all four limbs started along with respiratory distress, the potassium level was normal at that time. Another possible differential diagnosis was myasthenia gravis, but the antibodies to Acetylcholine Receptor (Ach-R) and muscle specific tyrosine kinase (anti-MuSK) were negative. Additionally, the result of the electrophysiological studies were not compatible with myasthenia. Transverse myelitis was ruled out on the basis of the findings on neurological examination, and absence of features suggestive of the condition on the MRI scan. Similarly, a normal MRI brain helped in ruling out encephalitis as well as any brainstem pathology.

Paraneoplastic phenomenon was another condition which was thought of. It was not possible to rule out this condition due to the non-availability of the tests that detected the auto-antibodies (namely, anti-ganglioside antibodies which can occur in small-cell lung cancer). She neither did have any features suggesting a malignancy nor any history suggestive of the same in the past.

Chronic inflammatory demyelinating polyneuropathy (CIDP) would have been considered if there would have been clinical progression for more than 8 weeks, or if there occurred two or more relapses in the future. During her hospitalisation however, the criteria for CIDP was not fulfilled.

Investigations (done following admission)

Her investigations revealed a haemoglobin of 129 g/L (normal range is 120–160 g/L), white blood cell count of 11x10⁹/L (normal range is 4–11x10⁹/L), platelet count of 310x10⁹/L (normal range is 1.5–4.5x10⁹/L), blood urea nitrogen of 11.9 mg/dL (normal range is 5–20 mg/dL), serum creatinine of 0.56 mg/dL (normal range is 0.5–1.5 mg/dL), sodium of 135.8 mmol/L (normal range is 135–145 mmol/L), potassium mmol/L (normal range is 3.5–5 mmol/L), bicarbonate of 22.3 mmol/L (normal range is 23–32 mmol/L), calcium of 9.3 mg/dL (normal range is 8.5–10.5 mg/dL) and magnesium of 2 mg/dL (normal range is 1.8–2.6 mg/dL). Her vitamin-D levels were normal.

MRI spine was done in view of the back pain which showed disc bulge at L3–L4 and L4–L5 levels which were indenting the thecal sac (figure 1) and compressing bilateral traversing L4, L5 nerve roots (figure 2). For her abdominal pain, CT abdomen was done which was normal.

Figure 1.

MRI spine showing disc bulge at L3–L4 and L4–L5 levels with the indentation of the thecal sac (yellow arrows).

Figure 2.

MRI spine showing compression of bilateral traversing L4, L5 nerve roots (yellow arrows).

Treatment

She received a total of five cycles of plasmapharesis (plasmapheresis was chosen as the modality of treatment over intravenous Ig due to the latter being expensive, and with the patient having financial restraints).

Outcome and follow-up

After the second cycle of plasmapheresis, she started to tolerate weaning, but she still had bilateral facial weakness, neck flexor weakness, with flaccid areflexic quadruparesis. However, the power in her ankle joint had improved marginally by then. By the end of her plasmapheresis therapy, she was extubated and was spontaneously breathing without any distress. Her facial and upper extremity weakness had recovered fully, but she required support to stand and walk. At the end of 8 weeks, complete recovery was seen, with no fluctuations in the blood pressure, and normalisation of sodium levels. The power in all her four limbs had become normal, and the deep tendon reflexes had become normal as well.

Discussion

GBS is a monophasic condition of acute onset occurring due to an immune response against an acute environmental trigger. In almost all the patients, the clinical nadir is reached by 4 weeks. The diagnosis of the condition involves clinical features and laboratory investigations.⁴ Examination of the CSF is a useful investigation, and GBS is characterised by albuminocytological dissociation picture of the CSF. This involves an elevated CSF protein coupled with a normal cell count. Sometimes, the protein level may be normal (especially within the first week), and in about 15% cases, there may be a mild increase in the cell count (approximately 0.005–0.05 cells x10⁹/L). Electrophysiological studies (nerve conduction studies) also help in diagnosing the condition, and also aid to differentiate between the axonal and the demyelinating forms of the disease. The Brighton criteria is useful to characterise the level of diagnostic certainty based on the clinical and investigation parameters.⁴ Our patient was categorised as level 1 of diagnostic certainty.

Autonomic involvement commonly complicates about 65% of cases of AIDP,⁵ especially in severe cases. There may be a variety of signs and symptoms due to the widespread distribution of autonomic fibres leading to sympathetic or parasympathetic failure or overactivity. There have been case reports which establish the link between GBS and hyponatraemia.^6–11

Euvolaemic hyponatraemia may occur secondary to syndrome of inappropriate ADH secretion (SIADH). The regulation of antidiuretic hormone (ADH) which is mediated by hypothalamus and autonomic nerve fibres, may be disrupted in GBS due to the autoimmune process leading to altered release patterns of ADH hormone, thus causing SIADH. In a prospective study involving 50 patients who were diagnosed with GBS, hyponatraemia was observed in 48% of cases¹² and motor dysfunction preceded the onset of hyponatraemia in all of them. There are other explanations for the pathogenesis of hyponatraemia in GBS which include impaired autonomic nervous function involving the afferent fibres from vascular stretch receptors, resetting of the osmostat,¹³ heightened sensitivity of the distal tubular and collecting duct ADH receptors, and also ADH independent mechanisms. The mean period of SIADH is usually 8.8 days after the symptoms of GBS start.¹³ In most cases reported in literature, hyponatraemia occurred after the diagnosis of GBS was established. Our case is unique in that hyponatraemia occurred 1 day before the onset of weakness, which could not be attributed to any other cause/process. Hyponatraemia in GBS is often associated with a poor prognosis.¹⁴ However, in our patient, despite the hyponatraemia, she responded well to treatment and recovered rapidly, with no residual neurodeficit.

Various types of pain have been reported in GBS¹⁵ although low back pain is common.^16–18Aetiology of low back pain is usually multifactorial. It might be related to impairment of peripheral nerves due to inflammation or changes in the denervated muscles.¹⁵ In our case, the low back pain in the acute phase led us away from the correct diagnosis. In addition to electrophysiological studies, CSF analysis may confirm a diagnosis of GBS. CSF protein concentrations in patients with GBS are often normal in the first week, but increased in more than 90% of patients at the end of second week¹⁹ as was seen in our patient. With regard to pain as a symptom in GBS, in just over a third of the patients,²⁰ it precedes the onset of the motor symptoms by about 2 weeks, as was seen in our patient.

Cardiovascular autonomic disturbances in GBS usually occur in those with diffuse motor involvement and may occur during the late progressive phase of the condition, as well as the plateau phase.^{21 22} In our case, hypertension and bradycardia started 8 days before the onset of motor weakness and persisted until the recovery phase, although well controlled with antihypertensive medications (telmisartan and amlodipine). Hypertension occurs in 60%–70% of patients with GBS²³ and marked fluctuations in the blood pressure is an indicator of poor prognosis. In our case however, the recovery of the patient was rapid, with a marked improvement in power. Although back pain can be one of the presenting features of GBS, it was overshadowed by the acute medical management of problems such as hyponatraemia and dysautonomia. Our patient’s altered mental status secondary to hyponatraemia contributed significantly to the delayed recognition of her limb weakness.

There are guidelines in place with regard to the management of GBS.²⁴ Features such as tachypnoea and tachycardia are indicative of imminent respiratory failure, and warrant intubation and mechanical ventilation, as was done in our patient. Dysautonomia may have various manifestations, such as gut dysmotility and fluctuations in the blood pressure.²⁴ Our patient manifested this in the form of a labile blood pressure. Hypotension was managed with intravenous fluids whereas hypertension was managed with nitroglycerine. Both intravenous Ig as well as plasmapheresis are effective therapeutic modalities.

Our case is an uncommon presentation of GBS in the sense that it presented in the form of autonomic disturbances and hyponatraemia before the weakness finally manifested.

Patient’s perspective.

I did not understand how and why all these problems started happening to my relative. Luckily for us, we consulted the doctor early, and the appropriate treatment was started, after which she started recovering.

Learning points.

• Sudden, unexplained autonomic disturbances should arouse the suspicion of the possibility of Guillain-Barre syndrome (GBS), even in the absence of flaccid paralysis at the time of onset.

• Although commonly following the onset of motor weakness, hyponatraemia may even precede it in GBS.

• In case of new onset back pain which occurs in the absence of any contributing or risk factor, GBS should always be kept in mind.