Hemisensory loss in myasthenia gravis

Abstract

A 73-year-old white man presents with left-sided ptosis and diplopia in the absence of ophthalmoplegia, with left hemibody paresthesia. He reports intermittent dysphagia and dizziness for 1 month and diarrhoea for 2 months. Serum and electrodiagnostic studies confirmed the diagnosis of myasthenia gravis. This case highlights the non-classic presentation of myasthenia gravis in the absence of ophthalmoplegia with a unique unexplained hemisensory deficit.

Background

Myasthenia gravis is a well-described autoimmune condition involving the acetylcholine receptors at the neuromuscular junction. First described by Dr Thomas Willis in 1672, the typical clinical syndrome associated with myasthenia gravis is well documented.¹ This condition is classically characterised by progressive muscle fatigability, especially affecting the ocular and bulbar muscle groups. The most common initial presentation consists of ptosis and diplopia.^{2 3} It typically begins with ocular and bulbar weakness and slowly progresses to respiratory failure in some patients. The highest incidence of the disease is seen in young women (first five decades of life) and older men (sixth, seventh and eighth decades).⁴ The overall inpatient hospital mortality for patients with myasthenia gravis is 2.2% and is higher in patients experiencing myasthenic crisis (4.47%).⁴ Patient age does not significantly affect the symptoms on presentation.⁵

Since the first characterisation of the disease several centuries ago, it has been regarded as one that does not present with sensory deficits. The current view remains that sensory changes are not features of myasthenia gravis.⁶ Interestingly, different sensory deficits in cases of myasthenia gravis have been identified in the literature, although generally rare. A recent review article on sensory deficits in myasthenia gravis documented changes in tactile skin perception (widespread), pain and changes in vision, taste, and smell.⁶

Although sensory deficits are not regarded as characteristic of the condition, myasthenia gravis has been correlated with development of comorbid neurological diseases. Documented comorbid neurological manifestations and neurological disorders include, but are not limited to, memory difficulties, sleep abnormalities, autonomic dysfunction, epilepsy, peripheral neuropathy, multiple sclerosis, dermatomyositis, neuromyelitis optica, dementia and psychiatric disorders. The current hypothesis for the development of these comorbid neurological diseases relates to the generalised cholinergic deficiency seen throughout the nervous system secondary to the myasthenic process.^{6 7}

Case presentation

A previously well 73-year-old man with a medical history of hypertension, type II diabetes mellitus, hyperlipoproteinaemia and sarcoidosis presented to the emergency department with a 1-month history of dysphagia. For the last 2 days, he complained of ptosis of the left eye, weakness and numbness of the jaw and left arm and sensory loss on the left side. He also reports having dizziness for 1 month and diarrhoea of unknown aetiology for 2 months.

Physical examination showed partial ptosis of the left side, decreased pinprick sensation of the left hemibody, decreased hearing (present prior to admission), decreased strength of the left upper extremity, 1+ reflexes bilaterally in the upper extremities and areflexia bilaterally in the lower extremities.

Patient consent was obtained for the collection and publication of details regarding this case.

Investigations

Studies included troponin on admission, complete blood count, MRI without contrast and a magnetic resonance angiogram of the brain and carotids without significant findings. Erythrocyte sedimentation rate and thyroid hormone levels were within normal limits. A non-contrast MRI of the brain was obtained in the emergency department. The brain MRI showed findings suggestive of age-related atrophy and mild chronic microvascular ischaemic changes. There was no evidence of acute infarct, haemorrhage, mass effect or extra-axial fluid collections. Specifically, diffusion-weighted imaging and apparent diffusion coefficient sequences showed no acute changes in the brainstem or thalamic region that correlate anatomically with the patient’s symptoms (figure 1).

Figure 1.

Axial cuts of diffusion-weighted imaging (A, C) and apparent diffusion coefficient (B, D) MRI sequences of the brainstem and thalamic regions. Images show absence of lesions suggestive of acute or chronic changes that correlate with the patient’s presenting symptoms.

Cerebrospinal fluid (CSF) analysis on the second day of admission showed protein of 52, glucose of 87 and no signs of meningitis. Anti-GQ1B antibodies were negative. CSF paraneoplastic panel (amphiphysin antibody, antiglial nuclear antibody (type 1), antineuronal nuclear antibody (types 1, 2 and 3), Collapsin Response-Mediator Protein-5-IgG and Purkinje cell cytoplasmic antibody (types Tr, 1 and 2)) and serum ACE level were within normal limits. CSF viral cultures for herpes simplex virus, varicella zoster virus, adenovirus and a fungal smear were all negative.

The ptosis present on the left side progressed to complete ptosis, with the right side showing partial ptosis by the third day of admission. At this time, he developed dysarthria, and his dysphagia worsened to the point of being unable to swallow his own secretions. The strength in his extremities progressively deteriorated, first involving only the left side and then becoming generalised with the proximal muscles affected more than the distal. He was then transferred to the intensive care unit due to concerns of respiratory insufficiency (negative inspiratory force=−35 and peak flow=420 mL). The patient was electively intubated for a head MRI with contrast and was subsequently unable to be extubated until 3 days later. The MRI showed no pathological enhancement. Cervical MRI showed no cord abnormality, multilevel degenerative changes in cervical spine and foraminal narrowing, which was asymmetrically prominent on the right. There was no spinal stenosis or signs of vertebral artery dissection.

Results of the myasthenia panel returned, and his acetylcholine receptor blocking antibody was 88 nmol/L, modulating antibody was 95% and binding antibody was 19.30 nmol/L consistent with a diagnosis of myasthenia gravis.

Nerve conduction testing showed evidence of a right-sided carpal tunnel syndrome and sensorimotor axonal loss polyneuropathy. Repetitive nerve stimulation did not show any evidence of neuromuscular junction disorder.

Differential diagnosis

The patient was initially monitored for a wide differential including myasthenia gravis, Guillain-Barre syndrome, stroke, neurosarcoidosis and brainstem lesion. At presentation, the findings of his neurological examination were not classic for any one of the items on the differential, but early CT and MRI were sought to rule out the more urgent diagnosis of a brainstem lesion. Stroke was thought to be a less likely cause of this patient’s condition due to the inability to attribute his constellation of symptoms to one focal neurological lesion, neuroimaging unremarkable for signs of cerebrovascular accident and eventual spontaneous resolution. Neurosarcoidosis was considered given the patient’s clinical history. However, when he presented to the emergency department, there was no documentation of chronic respiratory symptoms or signs of lymphadenopathy on chest radiograph. In addition, other studies showed a normal ACE level, and MRI showed no signs of lesions suspicious for neurosarcoidosis. At the time of presentation and until later in the admission, the two remaining items on the differential, myasthenia gravis and Guillain-Barre syndrome, were indistinguishable. However, the immediate treatment for these two syndromes was identical allowing further time to determine the underlying aetiology.

Treatment

The patient was started on pyridostigmine 60 mg three times a day on the first day of admission with minimal response. On his third day of admission, intravenous immunoglobulin (IVIG) 400 mg/kg/day was begun for the presumptive diagnosis of myasthenia gravis versus Guillain-Barre syndrome After the first dose of IVIG, examination showed return of reflexes in both the upper and lower extremities. By the time of the third IVIG dose, the ptosis and muscle weakness had resolved completely. He continued to have difficulty swallowing his oral secretions. Sensation remained unchanged until resolution after his third dose of IVIG.

On the seventh day of his admission, he received his last dose of IVIG. The following day, he was reintubated due to difficulty swallowing and an increase in oral secretions. No ptosis was present at this time, but he continued to have both dysphagia and dysarthria.

He remained intubated and sedated but was able to follow verbal commands when awakened. At this time, he was not in acute distress. He was started on prednisone 60 mg orally once a day, pyridostigmine 60 mg four times a day, glycopyrrolate 1 mg three times a day pro re nata for hypersecretion, piperacillin–tazobactam for aspiration pneumonia prophylaxis, proton pump inhibitor for gastric ulcer prophylaxis and deep vein thrombosis prophylaxis with heparin.

The next day, he was successfully extubated and continued having dysphagia and remained non per os. He received medications and caloric replacement via nasogastric tube.

He was discharged on prednisone 60 mg orally once a day and pyridostigmine 60 mg four times a day.

Discussion

Myasthenia gravis is an autoimmune disorder characterised by fatigue and muscle weakness especially affecting the ocular and bulbar muscle groups, with relatively preserved sensory modalities.³ In this condition, diplopia and ptosis are among the presenting symptoms in over 50% of patients.⁸ Myasthenia gravis is well documented as a condition that can present atypically or as an imitator of many other diseases and conditions, increasing the difficulty in diagnosing due to the wide number of rare presentations. Similar cases of myasthenia mimicking other conditions include stroke, isolated ocular findings, blepharospasm, pseudointernuclear ophthalmoplegia and vocal fold paralysis. However, none of these reports mention any form of sensory deficit.^9–13 This patient, while lacking the typical signs of ophthalmoplegia and diplopia, possessed a unique hemisensory loss.

Sensory loss is generally not accounted for in the presentation of myasthenia gravis, with the overall consensus being one of preservation of the sensory components.⁶ We believe this to be a misconception as sensory dysfunction has been documented as part of some cases myasthenia gravis. The earliest identified documentation of sensory changes in this condition was in 1957.¹⁴ Sensory abnormalities that have been described in myasthenia gravis include tactile and corneal perception and decreased smell, taste and audition. Numbness and tingling are found in 10% of patients with myasthenia gravis, and pain is present in 50% of autoimmune myasthenia gravis cases.⁶ Sensory neuropathies with decreased amplitude in sensory nerve action potentials have also been identified. Autonomic dysfunction is common in myasthenia gravis as well.⁶ The numbness may be associated with loss of myelinated and unmyelinated fibres as shown in sural nerve biopsy of patients with myasthenia gravis, although rare.⁷ Sensory symptoms improve with myasthenia gravis therapies including acetylcholinesterase inhibitors, immunosuppression and thymectomy, indicating that the abnormalities are part of the myasthenia gravis syndrome rather than a coincidental factor.⁷ The pathophysiology of these sensory changes remains unclear, but the autoimmune response appears to be related to nicotine receptor antibodies as well as antineuronal antibodies that react with the dorsal root ganglia, as seen in 50% of patients with sensory dysautonomia.⁶ Immune and genetic abnormalities of the proteins involved in cholinergic synaptic pathways such as rapsyn, titin, muscle-specific kinase, lipoprotein receptor-related protein, laminin, agrin, soluble N-ethylmaleimide sensitive factor attachment protein Receptor (SNARE) complex and butyryl cholinesterase are also implicated in the genesis of sensory abnormalities in myasthenia gravis.⁶ Given the current understanding of sensory abnormalities in myasthenia gravis, it is unclear why the sensory change affected only this patient’s left hemibody. Although patients with myasthenia gravis have been shown to have decreased tactile perception in the skin compared with the general population, this is present across the entire body.⁶ Based on our literature review, no presentations similar to this one, with a distinct hemisensory loss, have been identified in the literature. There have also been combined sensorimotor myasthenia gravis conditions described before, but generally, they present in the distal extremities bilaterally.¹⁵ Overall, these cases are exceedingly rare.

Since sensory changes in myasthenia gravis are hypothesised to be related to the generalised cholinergic deficiency of the nervous system, many of the sensory disturbances seen are present uniformly across the body, as in the case of the tactile deficits in the skin.⁶ In this patient’s case, the distribution of sensation loss, left hemisensory, suggests the potential for another mechanism with selective involvement of sensory nerve fibres. The strict division of the sensation loss on one-half of the body implies that the sensory deficit may arise from a different pathophysiological process than what is currently known in myasthenia. In this case, the localisation of the deficit does not correlate to the mechanism by which myasthenia gravis is thought to cause neurological deficits. At the time of publication, the authors did not have any specific evidence to suggest what the alternative mechanism is.

The way this case presented itself is more classic of the variants of Guillain-Barre syndrome. There are numerous variants that can present with differing sensory deficits, most commonly those along the Miller-Fisher syndrome–Bickerstaff brainstem encephalitis spectrum. Table 1 shows the main differences between myasthenia gravis and Guillain-Barre syndrome and its variants.¹⁶ The fact that he has a presentation of dysphagia with positive acetylcholine receptor antibodies, absent anti-GQ1B antibodies and lack of albuminocytologic dissociation in the CSF makes the diagnosis myasthenia gravis rather than one of a Guillain-Barre syndrome variant.

Table 1.

Symptomatic presentation of myasthenia gravis and Guillan-Barre syndrome variants

	Antibodies	Motor	Sensory	Reflexes	Autonomic involvement	Associations
Myasthenia gravis	Antiacetylcholine receptor	Bulbar weakness and fatigability	Preserved	Intact	Sometimes	Thymoma
Guillain-Barre syndrome	Varies (antiglycolipid)	Ascending symmetrical weakness	Paresthesias Diminished sensation	Hyporeflexia Areflexia	Yes	Diarrhoeal illness
Miller-Fischer syndrome	Anti-GQ1B	Ataxia, ophthalmoplegia	Mild peripheral neuropathy	Hyporeflexia Areflexia	Yes
Bickerstaff brainstem encephalitis	Anti-GQ1B	Flaccid tetraplegia	Hemisensory loss	Variable	Yes

In this case, the patient presented with symptoms that are not classic for myasthenia gravis, a left hemibody sensory loss. The presentation appeared to straddle the border between two similar conditions, myasthenia gravis and variants of Guillain-Barre syndrome, showing the importance of considering both disorders in these overlapping syndromes.

Learning points.

• This is a rare presentation of a classic disease. Myasthenia gravis generally presents with preservation of sensation; however, it can present with hemisensory loss.

• Hemisensory loss has been identified in Guillain-Barre syndrome but never documented in myasthenia gravis.

• Myasthenia gravis may present in a similar fashion to the rarer variants of Guillain-Barre syndrome (Miller-Fischer syndrome and Bickerstaff brainstem encephalitis).