A Rare case of recurrent Guillain-Barré syndrome without albuminocytological dissociation

Abstract

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy, often preceded by an illness. It is a self-limiting illness in most of the cases, but recurrence is rare and can be seen in about 1%–6% of patients. GBS is characterised by progressive, symmetrical, proximal and distal weakness. Areflexia and sensory disturbances are also common. Patients with GBS usually have albuminocytological dissociation on cerebrospinal fluid (CSF) analysis. This is a case of a 69-year-old woman with recurrent GBS and normal CSF findings.

Background

Guillain-Barré syndrome (GBS) is a rare autoimmune neuropathy that is considered to be a monophasic illness. However, recurrence of GBS can be seen in about 1%–6% of the cases. One of the classical findings in the setting of GBS is the albuminocytological dissociation in the cerebrospinal fluid (high protein in the setting of normal cell count), and the lack of such is also not common. We present a case of recurrent GBS that did not have albuminocytological dissociation both at the initial presentation and during the recurrence. Our case demonstrates the importance of good clinical history, physical and electrophysiological examination, and a low index of suspicion in identifying such a rare presentation.

Case presentation

A 69-year-old woman presented with bilateral lower extremity weakness and sensory disturbances in April 2018. She had a similar episode in January 2017.

A 69-year-old woman was admitted with subacute onset of bilateral upper and lower limb weakness and numbness for 3 weeks in January 2017. These symptoms were preceded by an upper respiratory tract infection. She had difficulty with walking, getting out of the chair, shuffling her feet, near falling and imbalance. There was no dysphagia, dysarthria, respiratory difficulty and bowel/bladder involvement. Physical examination showed a 4/5 Medical Research Council (MRC) grade strength in all the limbs with areflexia in bilateral upper and lower extremities. Sensory examination showed diminished sensation to pinprick in bilateral glove and stocking distribution.

Nerve conduction studies (NCSs) were performed 4 weeks after symptoms onset, and it was consistent with acute inflammatory demyelinating polyradiculopathy (GBS) (table 1) (figure 1). CSF analysis was also performed during the same time and was normal (table 2). She was started on intravenous immunoglobulin (IVIG) 0.4 g/kg for 5 days which showed significant subjective improvement in the lower extremity weakness, and she was able to ambulate using a walker. Her MRC grade strength at discharge was 5/5 throughout although she still had minimal tingling sensation in both hands and feet at the time of discharge.

Table 1.

Comparison of nerve conduction studies during initial and recurrent Guillain-Barré syndrome

Nerve/sites		Recording site	Distal latency (ms)	Amplitude (mV)	Conduction velocity (m/s)
Nerve conduction study during initial presentation of GBS in 2017: 1st episode
Sensory nerve conduction study
Median/wrist (right)		Digit II	–	–	–
Sural/posterior calf (right/left)		Calf	–	–	–
Motor nerve conduction study
Median (right)	Wrist	APB	5.9 (ref<4.2)	2.2 (ref>4.0)	–
	Elbow	APB	13.8	1.8	29.3
Peroneal (right)	Ankle	EDB	5.0 (ref<6.0)	2.2 (ref>2.5)	–
	Fibula	EDB	15.7	0.5	31.0
	Knee	EDB	20.0	0.4	23.0
Tibial (right)	Ankle	AH	16.0 (ref<6.6)	1.0 (ref>2.0)	–
	Knee	AH	29.5	0.6	29.4

Nerve conduction study during recurrence of GBS in 2018: 2nd episode
Sensory nerve conduction study
Radial/forearm (left)		Snuff	–	–	–
Sural/posterior calf (right/left)		Calf	–	–	–
Motor nerve conduction study
Median (left)	Wrist	APB	5.1 (ref<4.2)	3.1 (ref>4)	–
	Elbow	APB	14.8	1.5	24.7
Peroneal (left)	Ankle	EDB	6.7 (ref<6)	1.1 (ref>2.5)	–
	Fibula	EDB	17.2	0.2	32.8
	Knee	EDB	23.5	0.1	15.9
Tibial (left)	Ankle	AH	–	–	–

F-wave study
Nerve	M latency (ms)	F latency (ms)
Peroneal (right)	6.4	61
Reference		<57
Tibial (right)	17.3	70.6
Reference		<58
Median (left)	6.7	25.0
Reference		31

For sensory nerve conduction study, amplitude is measured peak-to-peak, the latency reported is the peak latency. For motor nerve conduction study, amplitude is measured baseline-to-peak, the latency reported is the distal onset latency. F-wave latency is the minimum latency.

Unless otherwise noted, the hand temperature was monitored continuously and remained between 32°C and 36°C, and the foot temperature was maintained between 30°C and 36°C during the performance of the nerve conduction study.

AH, abductor hallucis; APB, abductor pollicis brevis; EDB, extensor digitorum brevis; GBS, Guillain-Barré syndrome; ref, reference.

Bold values are deviations from the stated reference values.

Figure 1.

Nerve conduction study during the first episode. (A) Shows motor nerve conduction study of the tibial nerve at ankle and knee. Conduction block is seen both at the ankle and knee (black arrows). (B) Shows nerve conduction study of the median motor nerve at elbow and wrist. Prolonged latency is seen at the elbow (red double-headed arrow). (C) Shows F-wave latency of the tibial nerve. It shows impersistence (red arrowheads).

Table 2.

Cerebrospinal fluid (CSF) findings during initial presentation in 2017 and recurrence in 2018

CSF profile	2017—Initial GBS presentation	2018—Recurrent GBS
CSF glucose (mg/dL) (normal: 40–70 mg/dL)	65	60
Proteins (mg/dL) (normal: 15–45 mg/dL)	32	42
White blood cells/L (normal: 0–5 X 106/L)	3 X 106	0
Neutrophils %	9	NP
Lymphocytes %	91	NP
Red blood cells (µL)	12	1

GBS, Guillain-Barré syndrome; NP, not performed.

More than 1 year later, in April 2018, the patient was readmitted with subacute (14 days) onset of bilateral lower extremity weakness, numbness and paresthesias. Two months before the onset of symptoms, the patient had a gallbladder infection. On examination, there was generalised areflexia with an MRC grade muscle power of 4/5 in upper limbs and 2/5 in lower limbs. NCS was performed which showed evidence of a demyelinating polyneuropathy (table 1) (figure 2). CSF analysis was done, and it did not reveal albuminocytological dissociation (table 2). She was treated with IVIG 0.4 g/kg for 5 days without any improvement in the symptoms. Plasmapheresis was initiated and showed improvement on the following day. Her strength was 5/5 in the right upper extremity, 4/5 in the left upper extremity and 3/5 in lower extremities. Patellar reflexes were still absent in lower extremities bilaterally. Sensations were intact bilaterally at discharge.

Figure 2.

Nerve conduction study during the second episode. (A) Shows motor nerve conduction study of the median motor nerve at elbow and wrist. Temporal dispersion is seen at the elbow (red double-headed arrow). (B) Shows motor nerve conduction study of the peroneal nerve at ankle, head of fibula and the knee. Prolonged latency is seen at the ankle (black double-headed arrow). (C) Shows F-wave latency of the peroneal nerve. It shows prolonged latency, chronodispersion (black arrowheads) and impersistence (red brace).

Outcome and follow-up

• On the first presentation of GBS, she showed significant subjective improvement with IVIG in the lower extremity weakness and was able to ambulate using a walker. Her MRC grade strength at discharge was 5/5 throughout.

• During the second presentation, that is, recurrent Guillain-Barré syndrome (RGBS), she showed improvement with plasmapheresis. Her strength on follow-up was 5/5 in the right upper extremity, 4/5 in the left upper extremity and 3/5 in lower extremities with intact sensations bilaterally.

DISCUSSION

GBS is an acute immune-mediated polyneuropathy characterised by progressive, symmetric muscle weakness accompanied by diminished or absent deep tendon reflexes. In 1916, Georges Guillain, Jean-Alexandre Barré and André Strohl described this clinical syndrome in two soldiers with acute motor weakness and areflexia. They noted an increase in CSF protein levels with normal cell count (albuminocytological dissociation).¹ GBS is rapidly progressive and typically a monophasic disease (<4 weeks) often preceded by an infection. Two-thirds of adult patients report antecedent illness, most commonly respiratory or gastrointestinal tract infection.^{2 3} The estimated overall incidence of GBS in the USA is 1.65 to 1.79 per 100 000 population.⁴ The clinical presentations of GBS^{4 5} is shown in box 1.

Box 1. Clinical presentations in Guillain-Barré syndrome (GBS).

• Pain due to inflammation of nerve roots (typically back and leg) can be the presenting symptom of GBS.

• Bilateral and symmetric weakness in both upper and lower extremities.

• Paresthesias commonly accompany the weakness in more than 80% of patients.

• Decreased or absent reflexes are seen in approximately 90% of patients.

• Respiratory muscle weakness that may require ventilatory support can develop in 30% of patients.

• Facial nerve paralysis can develop in up to half of the patients.

• Autonomic dysfunction can be seen in up to 70% of patients. Cardiovascular dysregulation is common and can lead to bradyarrhythmias. SIADH is another complication and is more frequent in hospitalised patients.

The mechanism of GBS is thought to be due to molecular mimicry.⁶ An antecedent infection produces antibodies that cross-react with specific gangliosides and glycolipids, which are present in the myelin of peripheral nervous system. The end result is demyelination and blockade of conduction along the nerve.

GBS usually progresses over a period of 2 weeks and reaches a nadir in 4 weeks in almost all patients.⁶ Although rare, recurrence of GBS has been reported in 1%–6% of patients following an asymptomatic period of few months to years (4 months to 10 years).^{7 8} RGBS is characterised by two or more episodes, with a complete or near-complete recovery between episodes and clinical manifestations lasting ≤4 weeks.⁹ Immunological host factors or genetics could be implicated in RGBS and patients tend to have similar presentations in the initial as well as RGBS.⁹

It is important to distinguish RGBS from chronic inflammatory demyelinating polyneuropathy (CIDP), and GBS–treatment-related fluctuation (GBS-TRF) as the treatment differs between them (table 3).¹⁰ CIDP is characterised by progression or relapse of clinical symptoms beyond 8 weeks from the onset. CIDP also has fewer antecedent events and more sensory signs compared with GBS.¹¹ This is less likely in our patient due to the acute presentation, normal CSF protein and electrodiagnostic evidence of acute demyelinating polyneuropathy (AIDP). GBS-TRF is defined by secondary deterioration after initial improvement within the first weeks or months after onset of disease.¹⁰ Our patient was asymptomatic for a year before the recurrence which favours RGBS rather than GBS-TRF.

Table 3.

Differentiating features between GBS, GBS-TRF, A-CIDP and CIDP

Characteristics	GBS	GBS-TRF	A-CIDP	CIDP
Time to reach maximum severity (nadir)	Within 4 weeks	<2 weeks (maximum 4 weeks)	4–8 weeks, followed by a chronic course	>8 weeks
Disease course	Monophasic	One or more deteriorations after initial improvement or stabilisation following plasma exchange or IVIG	>2 deteriorations or deterioration after 8 weeks	Progressive, relapsing–remitting, steadily progressive or monophasic
Ventilator dependence	20%–30%	20%–30%	Very rare	Very rare
Cranial nerve deficits	Common	Common	Less common	Less common
Sensory, motor, autonomic involvement	Motor involvement more prominent Autonomic dysfunction more frequent	Same as GBS	Sensory signs more prominent Rarely autonomic involvement	Same as A-CIDP
Response to IVIG	Good	Good, with fluctuations	Variable	Good
EMG/NCS	Sometimes no classification possible at first EMG/NCS	Sometimes no classification possible at first EMG/NCS	Often demyelinating polyneuropathy at first EMG/NCS	Demyelination
Treatment	IVIG or plasma exchange	Repeat IVIG or plasma exchange	IVIG or plasma exchange, on confirmed diagnosis of CIDP consider prednisolone maintenance treatment	IVIG, prednisolone or plasma exchange

Adapted/modified by permission from Springer Nature, Nature Reviews Neurology, Guillain–Barré syndrome: pathogenesis, diagnosis, treatment and prognosis, Bianca van den Berg, Christa Walgaard, Judith Drenthen, Christiaan Fokke, Bart C. Jacobs et al. 2014 (doi:10.1038/nrneurol.2014.121).

A-CIDP, acute-onset chronic inflammatory demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; EMG, electromyography; GBS, Guillain-Barré syndrome; GBS-TRF, Guillain-Barré syndrome with treatment-related fluctuation; IVIG, intravenous immunoglobulin; NCS, nerve conduction study.

The diagnosis of GBS is based on clinical presentation and is supported by spinal fluid analysis and electrodiagnostic studies. CSF studies reveal elevated CSF protein with normal cell counts called albuminocytological dissociation. Our patient had normal CSF protein levels even after more than a week of illness during both episodes. On review of literature, one other case was reported with normal CSF findings during both the initial and recurrent GBS in a 25-year-old Sri Lankan woman who presented 12 years after complete recovery of AIDP variant of GBS with acute, ascending symmetrical flaccid quadriparesis extending to bulbar muscles, bilateral VII cranial nerves and respiratory compromise needing mechanical ventilation.¹²

IVIG or plasmapheresis is the mainstay of treatment in the acute phase of GBS.^{13 14} The beneficial effects of plasma exchange and IVIG are very similar.¹⁵ The combination of both does not confer any more benefit.¹⁶ Besides the treatments mentioned above, no pharmacological agents are found to be effective in GBS.¹⁷ Glucocorticoids are ineffective¹⁸ in the treatment of GBS. In fact, these should not be used as it may slow down recovery.¹⁹

The patient was initially treated with pooled immunoglobulin (IVIG) for 4 days which did not hasten the recovery, and because we were worried about complications from immobility, we started her on plasma exchange. She underwent five sessions of plasmapheresis on alternate days which showed significant improvement in her symptoms.

Learning points.

• It is important to have a high index of suspicion of recurrent Guillain-Barré syndrome in patients who present with bilateral weakness, sensory disturbances and previous history of GBS.

• Recurrence of GBS is seen in patients even after months or years of asymptomatic period.

• Cerebrospinal fluid findings can be normal during both the initial and recurrent episodes of GBS. Thus, clinical history, thorough examination along with electrodiagnostic studies might be needed to confirm this.