ABSTRACT

Myasthenia gravis (MG) together with Lambert-Eaton myasthenic syndrome (LEMS) in the same patient is rarely described. This is a case report of a patient who initially presented with myasthenia gravis and later complicated with presumably auto-immune LEMS. The patient was noted to be HIV positive. The interest lies in the behaviour of MG in immunocompromised patients and the electrophysiological changes at the neuromuscular junction in patients with both MG and LEMS. We present a patient who is HIV positive with a long history of MG and a possibly a more recent diagnosis of LEMS.

Keywords : Myasthenia Gravis, Lambert Eaton myasthenic syndrome, HIV

RESUME

L’association myasthénie et syndrome de Lambert-Eaton chez un patient est rarement décrit. Nous rapportons le cas d’un patient, VIH positif, s’étant présenté initialement par une myasthénie, complétée ultérieurement par un syndrome de Lambert Eaton vraisemblablement d’origine auto-immune et discutons les liens éventuels, au plan pathogénique.

Mots clés : Myasthénie, syndrome de Lambert-Eaton, virus d’immunodéficience acquise, VIH

INTRODUCTION

Myasthenia gravis (MG) is a relatively common disorder affecting 3 per 105 people (7). This is an acquired postsynaptic disorder at the neuromuscular junction affecting acetylcholine receptors which are destroyed by an autoimmune process confirmed by the presence of acetyl choline receptor antibodies and a more recently identified anti muscle specific kinase antibodies.

Lambert Eaton myasthenic syndrome (LEMS) is also a neuromuscular junction disorder characterized by a presynaptic acetyl choline release deficit due to antibodies against the voltage gated calcium channels of the P/Q type. Approximately 90% of patients with LEMS are positive for this antibody.

Although the clinical presentations do overlap the frequency of symptoms vary. In a report by Wirth et al comparing 101 patients with MG and 38 patients with LEMS bulbar involvement was 59% in MG patients compared to 5% in LEMS patients. Limb weakness was more frequent in LEMS being 95% as opposed to 12% in Mg when patients first presented (21)

TABLE 1: clinical features (frequency at first presentation) (21)

We report a patient who initially presented with features consistent with MG and over a period of ten years developed features suggestive of LEMS.

CASE REPORT

A 21 year old woman presented with fluctuating diplopia, ptosis, difficulty in swallowing and proximal upper limb weakness in November 1990. Examination showed bifacial weakness, bilateral external ophthalmoplegia and ptosis. There was proximal upper and lower limb weakness with preserved reflexes. Neck flexion and extension was weak. An edrophonium test was positive. A CT scan showed an anterior mediastinal mass consistent with an enlarged thymus. The patient was commenced on prednisone (60mg), pyridostigmine and subjected to transthoracic thymectomy. Histology showed thymus tissue with chronic stress involution. Over the following 10 years, she required four further admissions for exacerbations attributed to poor compliance with medication and a failed thymectomy as the repeat CT scan showed a residual thymic tissue for which she had a repeat transthoracic procedure. On this occasion the histology showed a similar picture. During the period under our care the patient was maintained on prednisone in doses varying from 80mg during relapses to 20mg during periods of clinical improvement. She was never below 20mg daily. In addition she continued to take azathioprine at doses varying from 50 to 100mg daily. During relapses with deterioration she received pulsed weekly doses intravenous cyclophosphamide at 10mg / kg for up to 4 doses. She was maintained on pyridostigmine throughout the period. Nine years following initial assessment arreflexia was noted. She complained of occasional dry mouth. This prompted further evaluation for a neuropathy. Her repeat nerve conduction studies (NCS) demonstrated normal conduction but low compound muscle action potential (CMAP) amplitudes without denervation or myopathic changes on electromyography (EMG). The results of the repetitive nerve stimulation (RNS) are illustrated in the following table. Recordings were obtained from Abductor Pollicus Brevis.

TABLE 2: Electrophysiological findings

ND = Not done. MG: Myasthenia gravis, CMAP: compound muscle action potential, Grade 2A refers to the clinical myasthenic severity grading as defined by Osserman classification (6)

Serology for Acetylcholine receptor antibodies was positive at 79 (10-10M) (normal: 0-5). Voltage gated channel antibodies were negative. These were done in July 2001. The thyroid function tests were normal. Antinuclear antibodies were not detected. However, she was found to be HIV seropositive in 2001. The CD4 count at this time was 854 (normal=550 to 1955). The absence of reflexes, the low CMAP amplitudes and the greater than 200% increment on RNS suggested LEMS. A neuropathy was unlikely as she had no accompanying sensory disturbance and the nerve conduction studies were normal except for the low CMAP and there was no spontaneous activity on EMG.

DISCUSSION

That the patient had features of MG was established by appropriate clinical, electrophysiological and serological tests. The later development of hyporeflexia and low amplitude CMAPs suggested the co-existence of LEMS in this patient. Several features confirm this possibility. The development of arreflexia with elicitation of reflexes following exercise, the low CMAP amplitudes with single peripheral nerve stimuli, normal EMG and the >100% increment at high frequency repetitive nerve stimulation are consistent with LEMS (6,7). This patient fulfilled the diagnoses of MG and LEMS as outlined by the American Association of Electrodiagnostic medicine (7)
The criteria for the diagnosis of Myasthenia Gravis and LEMS as established by the are a reproducible 10% decrement in amplitude when comparing the first to the fourth or fifth stimulus provided that anticholinesterase medication is withheld 12 hours prior to testing and the frequency of stimulation is between 2 and 5Hz, for MG and a reproducible post exercise increase in amplitude of at least 100% as compared to baseline pre exercise values for LEMS.
Recommendations for single fibre EMG are not relevant to this patient as this was not done. This patient satisfied the electrophysiological and clinical criteria for both Myasthenia Gravis and LEMS as demonstrated in the table.

The co-occurrence of Myasthenia Gravis and LEMS has been previously described however there have been only a few reports (8,13,18). Shin J Oh et al reported their experience with a single patient and refer to 2 other patients. In these references the patients described by Newsom Davis et al satisfy the criteria for the diagnosis and was confirmed by antibody tests in both cases mentioned.
The occurrence of HIV seropositivity may be a chance association as the total population incidence is 33-35% within the African population (19). The combination of HIV and Myasthenia Gravis has been previously documented (3,4,5,20). Verma et.al. (3) reviewed 6 cases with Myasthenia Gravis and HIV and in these patients CD4 counts varied between 371 and 1067. The patients generally manifested and followed a course consistent with myasthenia Gravis. It is most likely that in our patient HIV is not likely part of the pathogenesis of Myasthenia Gravis. Our patients CD4 count was fairly high (854) and the duration of Myasthenia Gravis was over 10 years making a coincidental occurrence likely. It is likely the Myasthenia Gravis preceded the HIV seropositivity. Experience with the co-occurrence of Myasthenia Gravis and HIV is limited worldwide but as immunity wanes one intuitively expects the Myasthenia Gravis to remit.

HIV may in itself complicate with neuropathies notably AIDP and CIDP earlier in the course of disease and a painful sensory neuropathy later in the course of HIV disease. Additionally infection with herpes zoster, CMV also results in polyradiculopathies. Lastly mononeuropathies have also been described in HIV disease, however our patient did not have a neuropathy. Myopathies complicating both HIV disease itself (inflammatory myopathy) and related to HAART therapy (mitochondrial myopathy) needs consideration but this was clinically unlikely in this patient.

Acetylcholine receptor antibodies are present 86% of patients with generalised MG and only 71% in ocular MG (11,12). In patients who are negative for acetylcholine receptor antibodies more recent studies have confirmed muscle specific kinase antibodies contribute to the development of myasthenia gravis (MuSK) (1). This is a tyrosine kinase that plays a role in acetylcholine receptor clustering. The sensitivity of voltage gated calcium channel antibodies, usually of the P/Q type is 90%. Acetylcholine receptor antibodies have been described in 5% to 13% of patients with LEMS (11,12). Recent reviews have confirmed that the N and L types are not constitutively expressed at the neuro-muscular junction but are expressed during development and re-innervation (2). This patient was on immunosuppressive therapy for a prolonged period before the arreflexia developed. One possibility is new antibodies to N and L type channels with therapy. Another is the occurrence of antibodies as a non-specific immunoglobulin production seen in patients who are HIV positive as in this patient. There have been several case reports of patients with coincident MG with HIV infection (3, 4). Single case reports have suggested resolution or decreased severity of MG as HIV progresses (4). Presumably, with the deteriorating immune status, there is a decline in the production of acetylcholine receptor antibodies. Finally MG has been described as a transient complication of HIV presumably as a result of molecular mimicry in the HIV antibody generation process (9).

There have been previous reports of incremental responses in MG but not greater than 100% (4,15). There has been a single report of a patient with typical MG who has an incremental response beyond 100%. The explanation for this remains elusive (3). This patient did not have antibody tests. In our patient the arreflexia and the emergence of reflexes following exercise lends support to LEMS. The increment implies enough post-synaptic reserve to allow for this despite the myasthenic defect. However, the process at the post-synaptic membrane in a patient with both diseases is unknown. The predominant abnormality is post-synaptic as this patient had clinical MG initially. Perhaps theoretically there are influences on channel opening and closing times post-synaptically, investigation of which would elicit an explanation. This information is presently not available.

CONCLUSION

This patient illustrates a possible changing autoimmune profile over time, initially presenting with MG followed by the development of LEMS. It is unknown whether the HIV seropositivity had an influence on the evolution of her illness.