Two cases of myasthenic syndrome with thymoma, polymyositis, myocarditis, and thyroiditis

A clinical and pathological study of 2 cases of a myasthenic syndrome in patients with an unusual combination of multiple visceral lesions (thymoma, polymyositis, myocarditis and thyroïditis) is reported. Histological study of these 2 cases emphazises that a myasthenic syndrome should be considered as the result of an auto-immune disease, but also that the thymus can be a target organ in the pathological process.     

Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome

Stiff-person syndrome (SPS) is a disorder characterized by progressive muscle rigidity with superimposed painful muscle spasms and gait impairment due to continuous motor activity. Evidence has accumulated in favor of SPS representing an autoimmune, predominantly encephalomyelopathic disorder resulting from B-cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the enzyme glutamic acid decarboxylase (GAD) and the synaptic membrane protein amphiphysin. Recognition of the clinical spectrum of SPS is important, particularly the upper-limb, cervical, and cranial nerve involvement that occurs in paraneoplastic variants. The correlation between antibody levels and severity of disease offers evidence for a pathogenic role for the anti-GAD and anti-amphiphysin autoantibodies. The scarcity of neuropathological correlates stand in sharp contrast with the severity of the disability in affected individuals and suggests that functional impairment of inhibitory circuits without structural damage is sufficient to develop the full clinical spectrum of SPS. The rarity of this condition limits the feasibility of controlled clinical trials in the treatment of SPS, but the available evidence suggest that drugs that increase cortical and spinal inhibition such as benzodiazepines and drugs that provide immune modulation such as intravenous immunoglobulin, plasmapheresis, and prednisone are effective treatments.     

Concurrence of myasthenia gravis, polymyositis, thyroiditis and eosinophilia in a patient with type B1 thymoma]

We presented a 43-year-old Japanese woman who acutely developed weakness of all extremities and difficulty in swallowing and drooping of eyelids, characterized by easy fatigability at the end of December, 2005. On general physical examination, she had moderate goiter. No cervical lymphadenopathy, cardiac murmur, or skin rash was noted. Neurologically, she had blepharoptosis, more on the right, only in the upright position with easy fatigability and marked weakness in the neck flexor, trunk, and all limb muscles much more proximally than distally. She had neither muscular atrophy nor upper motor neuron sign. Laboratory data showed slight leukocytosis with eosinophilia (up to 31%), and serum creatine kinase was markedly increased to over 2,000 IU/l. TSH receptor antibody (11.9%) and anti-acetylcholine receptor antibody (46.6 nmol/L) were also increased. Edrophonium test was positive. Electrophysiologically, muscle evoked potentials by repetitive motor nerve stimulation showed 13% and 50% waning in abductor pollicis brevis and deltoid muscle, respectively, at low frequency and no waxing at high frequency. Needle EMG showed fibrillation potentials and positive sharp waves in proximal muscles. Polymyositis was diagnosed by muscle biopsy which showed infiltration of lymphocytes in the endomysium and around non-necrotic muscle fibers. Upper arm muscle MRI showed multifocal high signal intensity lesions on T2-weighted images which were likely related to myositis. This finding is atypical for polymyositis. X-ray and CT of chest showed a mass lesion in the left pulmonary hilum, which was histologically diagnosed as type B1 thymoma. Thus, the present case had myasthenia gravis, polymyositis, thyroidititis and eosinophilia associated with type B1 thymoma. After the thymectomy, corticosteroid administration and immunoadsorption therapy, clinical symptoms and all laboratory abnormalities markedly improved.     

Successful treatment in a patient with a focal form of stiff-person syndrome using plasma exchange and intravenous immunoglobulin therapy]

We report a 42-year-old female with continuous muscle stiffness and painful muscle spasms of the right leg. The symptoms developed suddenly and worsened over the week after onset. At hospitalization, the right leg had a fixed posture of extension and the foot was plantar-flexed and internally rotated. Neurological examination revealed hyperreflexia of the right knee with positive Chaddock's sign, and stiffness and painful spasms located in the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. She could not walk due to her stiffness. There were no signs of rigidity in the left leg, upper extremities, or truncal muscles. Electrophysiological examinations revealed continuous muscle discharge. High titers of anti-glutamic decarboxylase (GAD) antibodies were detected in serum (140,000 U/ml) and cerebrospinal fluid (1,347 U/ml), confirming that the patient suffered from stiff-leg syndrome. Systemic evaluation revealed no malignant neoplasm, but revealed euthyroid Hashimoto's disease. Stiff-leg syndrome in this case was unresponsive to pharmacotherapy with diazepam and was unchanged for the first month of hospitalization. Plasma exchange therapy alleviated the clinical symptoms and decreased the anti-GAD antibody titer. After IVIg therapy, the symptoms and signs have dramatically disappeared to date but the titer of anti-GAD antibodies in serum recurred after an initial fall. To our knowledge, this is the first case of stiff-leg syndrome in Japan.     

Polymyositis, myasthenic syndrome and thymoma in a patient with defective cell-mediated immunity.

We studied a 57-year old woman with severe myasthenic syndrome predominantly proximal. There was no therapeutic effect using cholinesterase inhibitors. Clinical findings, electromyography, whole body scanning and biopsy revealed polymyositis. Thirteen years before the patient was operated of a benign thymoma. The history of the patient showed numerous life threatening episodes of viral and fungal infections. Autoimmune anemia was diagnosed. Investigations of the immune system in vivo and in vitro revealed severe qualitative and quantitative defects in the lymphocyte population spontaneously forming rosettes with sheep red blood cells (SRBC). Thymoma, autoimmune disorder, such as polymyositis and myasthenia gravis, unspecifically elevated antibody titers, multiple severe viral and fungal infections and the defect of the cell-mediated immunity suggest a T-lymphocyte effector- and regulatory dysfunction in this patient.     

Rituximab in chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus

The authors report a 57-year-old patient with chronic inflammatory demyelinating polyneuropathy (CIDP) associated with diabetes mellitus (DM) who was treated successfully with rituximab. The B lymphocyte suppression using rituximab was followed 4 weeks later by neurological improvement and a stable disease course of over 10 months. We suggest that rituximab may be a treatment option in CIDP increasingly less responsive to intravenous immunoglobulin, particularly in patients with concurrent DM.     

Head retraction reflex-like movements with severe bulbar symptoms in a patient with stiff-person syndrome]

A 57-year-old woman developed muscular stiffness and painful cramps, which were relieved by administration of dantrolene sodium. Her serum level of antibodies to glutamic acid decarboxylase (GAD) was markedly elevated and continuous muscular activities were observed on resting surface EMG. These features were compatible with those in stiff-person syndrome (SPS). She was found to have thymoma on CT scan. Immediately after thymomectomy, which was histologically diagnosed as a benign hyperplasia, she developed head retraction reflex-like movements evoked by sensory stimulation to the face, which were followed by severe bulbar symptoms with dysphagia and respiratory arrest. Postoperative myasthenia gravis was excluded clinically. While somatosensory evoked EMG on splenius muscle initially showed biphasic responses with latency of 15 msec and 55 msec, respectively after oral angle non-painful electric stimulation, the late potential phase disappeared after the patient recovered from bulbar symptoms. This suggests that head retraction reflex-like movements of this patient reflected the attenuation of inhibitory potentials from the brainstem.     

Guillain-Barre syndrome in patient with Burkitt's lymphoma and type 2 diabetes mellitus

Although peripheral neuropathies are commonly observed in patients with non-Hodgkin's malignant lymphomas (NHML), Guillain-Barre syndrome (GBS) belongs to the occasional complications of lymphoproliferative disorders. It appears in less than 0.3 per cent of NHML. It is worthy of note that in the reported case there occurred three independent risk factors of peripheral neuropathy: Burkitt's lymphoma, chemotherapy and type 2 diabetes mellitus. Based on clinical course, EMG finding and neuropathological examination, in spite of normal cerebrospinal fluid protein content, GBS as a paraneoplastic disorder was diagnosed. It was assumed that chemotherapy and diabetes mellitus conduced to severe neuropathy.     

Down syndrome presenting with multiple sclerosis, thyroid dysfunction, and diabetes mellitus. Multiple autoimmune disorders in a genetic disorder

Down syndrome (DS) is one of the most common survivable chromosomal disorders, and is well known to be associated with multiple autoimmune diseases. Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. An association of DS and other autoimmune disease has been previously reported, and we report one case of DS in coexistence with MS, diabetes mellitus, and thyroid diseases. We suggest that MS, such as other autoimmune diseases, is prevalent in DS patients.     

A patient with steroid responsive encephalopathy associated with autoimmune thyroiditis

We present a 58-year-old female with gradual cognitive decline and gait instability over 6 months. Her motor examination was notable for myoclonus, brisk reflexes with flexor plantar responses, and a cautious gait without ataxia. Cognitive testing revealed mildly impaired attention, but profoundly impaired calculation, judgment and visual memory. There were no manifestations of autoimmune thyroid disease. Routine laboratory analysis was unrevealing. Cerebrospinal fluid analysis was remarkable only for an elevated protein of 0.64 g/L (normal <0.45 g/L). Electroencephalography demonstrated intermittent bitemporal slowing. Brain MRI with gadolinium demonstrated extensive bilateral subcortical and periventricular white matter T2-weighted and hyperintensity on fluid attenuated inversion recovery MRI. Elevated anti-thyroperoxidase antibody of 8.07 IU/mL (<5.61 IU/mL) and thyroglobin antibody of 9.85 IU/mL (<4.11 IU/mL) were found and steroid responsive encephalopathy associated with autoimmune thyroiditis was diagnosed. Methylprednisolone (1 g daily for 3 days) resulted in dramatic improvement in cognition and mobility, which remained on follow-up.     

A case of stiff-person syndrome,type 1 diabetes,celiac disease and dermatitis herpetiformis

Antibodies against glutamic acid decarboxylase (GAD) are involved in the pathophysiology of stiff-person syndrome (SPS) and type 1 diabetes. GAD catalyses the conversion of glutamate to gamma-aminobutyric acid (GABA). GABA acts as a neurotransmitter between neurones, while in pancreatic beta cells it plays an integral role in normal insulin secretion, hence the clinical presentation of muscular spasms in SPS and insulin deficiency in diabetes. Despite this apparent major overlap in pathophysiology, SPS only rarely occurs in individuals with type 1 diabetes. We report the case of a 41-year-old man presenting with a simultaneous diagnosis of both these conditions. His case is unusual in that it is the first reported case in the literature of these conditions occurring in someone with celiac disease (CD) and dermatitis herpetiformis. We discuss why SPS and type 1 diabetes co-exist in only a minority of cases and speculate on the underlying mechanism of the association with CD and dermatitis herpetiformis in our patient.     

Progressive encephalomyelitis with rigidity presenting as a stiff-person syndrome

Diagnosis criteria of stiff-person syndrome (SPS) include progressive, fluctuating muscular rigidity and spasms with normal neurological examination. The presence of unusual features such as prominent limb rigidity with segmental signs and contracture, evidence of brainstem dysfunction, profound autonomic disturbances, CSF pleiocytosis or MRI abnormalities in patients with SPS presentation allows to classify these patients as progressive encephalomyelitis with rigidity (PER). We report a 50 year-old woman suffering from severe painful spasms of abdominal wall and limb muscles. Neurological examination showed pyramidal signs. EMG disclosed continuous muscle activity with superimposed discharges. Treatment with high doses of diazepam and baclofen led to moderate improvement of generalised stiffness. However, the right arm became more rigid with oedema and vasomotor changes. Subsequently, bilateral nystagmus and internuclear opthalmplegia appeared. There was mild CSF pleiocytosis. Associated auto-immune thyroiditis was found with positive anti-microsome antibodies and decreased thyroid hormones. Search for profound neoplasm was negative. The patient had three subacute bouts then she improved with methylprednisolone. The initial clinical presentation mimicking a SPS with subsequent diffuse involvement of the central nervous system and a striking localisation of a severe rigidity to one arm allowed to suspect the diagnosis of PER. The relationship between SPS and PER remains unclear because of the rarity of these disorders. The observation reported in this paper gives evidence that both the disorders are probably two clinical presentations of the same pathogenic process.