Anti-amphiphysin positive stiff-person syndrome due to invasive ductal carcinoma in a male patient

Abstract

Stiff-person syndrome (SPS) is a rare progressive neurological disorder characterised by painful muscle spasms and progressive muscle rigidity, leading in some cases to impaired ambulation. Anti-amphiphysin positive SPS is a paraneoplastic variant, frequently associated with breast carcinomas and small cell lung cancers. We report the case of a 53-year-old patient who developed symptoms of anti-amphiphysin positive SPS 3 years before being diagnosed with invasive ductal carcinoma. Specifically, computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography-CT (PET-CT), mammogram, colonoscopy and magnetic resonance imaging (MRI) did not identify malignancy during the 3 years following the onset of symptoms. Following diagnosis of invasive ductal carcinoma and completion of curative-intent oncological treatment, the patient experienced improvement, though not complete resolution, in his SPS symptoms. This case highlights the importance of thorough oncological workup when clinical presentation and diagnostic testing are suggestive of anti-amphiphysin positive SPS.

Background

Stiff-person syndrome (SPS) is a rare, progressive neurological disorder characterised by painful muscle spasms and progressive rigidity of the axial and proximal limb muscles leading in some cases to impaired ambulation. The paraneoplastic presentation of SPS is a rare variant, comprising up to 5% of cases of SPS.¹ This variant has been shown to be associated with autoantibodies against a synaptic protein called amphiphysin.^{2 3} Anti-amphiphysin positive SPS is most commonly associated with breast carcinomas and small cell lung cancers.^{1 4 5} Male breast cancer is rare, comprising 0.5%–1% of all breast cancers diagnosed each year.^{6 7}

We report the case of a male patient who developed symptoms of anti-amphiphysin positive SPS 3 years before being diagnosed with invasive ductal carcinoma of the left breast.

Case presentation

A 53-year-old man initially presented to numerous outside hospitals with a rash, fatigue, stiffness in his legs and feet, cramping in his toes, episodic numbness of his hands and difficulty with dorsiflexion of his left ankle. The patient’s rash resolved with steroids but the remaining symptoms persisted. Over the course of several months, his symptoms continued to spread, eventually involving his left hip and then progressed up his right leg in a similar pattern. The patient denied double vision, changes in voice, difficulty swallowing, bowel or bladder incontinence and atrophy.

Shortly after symptom onset, the patient was evaluated by an outside Neurologist. At this time, neurologic physical exam demonstrated normal mental status and intact cranial nerve (II-XII) function. Muscle strength was documented as full (5/5) in all tested muscle groups of the upper and lower extremities. The patient had intact sharp, dull, and vibratory sensation. Coordination was determined to be within normal limits on finger-to-nose testing. The physical exam was significant for increased rigidity of the right arm (2+ rigidity), “slowness” of left arm and bilateral leg movements (specific movements regarded as “slow” not documented), episodic posturing of the left arm (shoulder partially abducted, elbow flexed and fingers abducted), a slow gait with normal stride length, and an ability to walk on toes and in tandem but with the patient voicing concerns about imbalance. At this time, it was documented that psychogenic dystonia was thought to be the most likely explanation of the patient’s symptoms.

Investigations

Initial workup was extensive and included laboratory testing and a lumbar puncture, revealing elevated protein and lymphocytic pleocytosis. Electromyography (EMG) testing conducted at outside hospital was reported as being within normal limits. Evaluation by a rheumatologist resulted in a diagnosis of presumed Lyme disease, for which the patient was treated with doxycycline. In addition, infectious workup suggested co-infection with Babesia and Bartonella which prompted a 3-month course of atovaquone, clarithromycin, nystatin, rifampin and hydroxychloroquine. Following this course of antibiotics, the patient reported mild, subjective improvement in his lower extremity symptoms but increasing difficulty with ambulation and new and progressive stiffness and pain involving his upper extremities.

A lumbar puncture ordered 2 years following the initial onset of symptoms was sent for paraneoplastic antibody and glutamic acid decarboxylase (GAD)-65 antibody testing to investigate for possible SPS. GAD-65 antibody was negative, but amphiphysin antibody titre was positive at 1:64 (reference range <1:2). The patient subsequently underwent CT of the chest, abdomen and pelvis, positron emission tomography-CT, mammogram, colonoscopy and MRI (brain and total spine) to investigate underlying malignancy, which were all interpreted as being within normal limits and without evidence of underlying malignancy. Subsequent repeat EMG testing was found to be consistent with SPS. Physical therapy, gabapentin and baclofen were started with minimal symptomatic improvement. Diazepam was trialled but discontinued due to psychotropic effects and no improvement in SPS symptoms. Due to increasing episodes of anxiety, clonazepam was prescribed, which functioned well as an anxiolytic but provided no SPS symptom relief. Intravenous immunoglobulin (IVIG) infusions were started with subsequent improvement in his overall mobility symptoms, including ambulation. However, the symptomatic improvement with IVIG would prove transient, with re-escalation of symptoms over the course of 1–2 weeks. Despite the presence of amphiphysin antibodies, the absence of an underlying malignancy on imaging workup led to a diagnosis of the more common autoimmune variant of SPS. In addition to future repeated cancer screening, the benefits of continued IVIG, rituximab and cyclophosphamide were discussed with the patient. The patient elected to begin cyclophosphamide therapy, which provided significant improvement in symptoms. Although some symptoms persisted, on physical examination the patient was found to have improved range of motion, mobility of his arms and legs and tone.

Three years following the initial onset of symptoms, a repeat chest CT was significant for a 1 cm left retroareolar nodule. Follow-up mammography was significant for a suspicious retroareolar left breast mass measuring up to 1.6 cm with likely intraductal extension. Left breast core biopsy demonstrated invasive ductal carcinoma. Evaluation for common breast cancer receptors found the tumour to be estrogen receptor (ER) and progesterone receptor (PR) positive, and human epidermal growth factor receptor-2 (Her-2-neu) negative. On directed axillary ultrasound one to two suspicious left axillary lymph nodes were identified and needle biopsy confirmed the presence of malignant cells in the lymph nodes. Genetic testing was negative for pathogenic germline variants in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RAD50, STK11 and TP53.

Treatment

In addition to the treatments described above, the patient underwent left modified radical mastectomy. The surgical pathology demonstrated a 2.2 cm invasive ductal carcinoma, histological grade 2 with 1 out of 11 axillary lymph nodes involved by 1.8 cm metastatic deposit with extranodal extension identified. Adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil was administered every 3 weeks for a total of six cycles. Taxane-based chemotherapy was avoided due to concerns of potential peripheral neuropathy further impairing the patient’s mobility. Following chemotherapy, the patient was treated with post-mastectomy radiation and adjuvant endocrine therapy with tamoxifen.

Outcome and follow-up

At the patient’s most recent follow-up, 1 year following surgery, he reported greatly improved upper extremity stiffness. However, the patient reported continued stiffness, cramps and unsteadiness of his lower extremities. The patient has continued with different gamma aminobutyric acid (GABA) modulating pharmacotherapies for management of his residual symptoms. In addition, the patient reported improvement in SPS symptoms after starting yoga and meditation.

Discussion

SPS is a rare progressive neurological disorder characterised by painful muscle spasms and progressive musculoskeletal rigidity leading to impaired ambulation.¹ Notably, emotional disruption, sudden movement and loud noises may precipitate muscle spasticity and are sensitive and specific for SPS.⁸ In addition, as documented in this report, patients with SPS may experience progressive anxiety as ambulation worsens.⁹ SPS is caused by reduced nervous system inhibition resulting in subsequent increased muscle activity. The pathogenesis of classic SPS is believed to be autoimmune in the vast majority of cases, with approximately 60%–80% of cases associated with anti-GAD antibodies targeting GABAergic neurons.^{1 10 11}

Paraneoplastic SPS comprises approximately 1%–5% of SPS cases and has been shown to be associated with autoantibodies against amphiphysin, a 128-kd protein associated with synaptic vesicles.^1–3 Notably, malignancy has been shown to be less common in patients with anti-GAD positive SPS.¹² Anti-amphiphysin positive SPS is classically associated with breast and small cell lung cancer although malignancies of the colon, thymus and Hodgkin’s lymphoma have also been reported.^{1 4 13} In addition, anti-amphiphysin positive SPS has been shown to have a female predominance.¹⁴ Paraneoplastic SPS has a similar clinical presentation to classic SPS, but may also be accompanied by symptoms of the underlying neoplasm.

Breast cancer is rare in men with an incidence between 0.5% and 1% of all breast cancers.^{5 6} Men with breast cancer typically present with a painless subareolar mass and the majority of male breast cancers are invasive ductal carcinomas.^{15 16} Like in their female counterparts, concurrent axillary lymph node involvement ipsilateral to the mass is indicative of more advanced disease. The rarity of male breast cancer, paraneoplastic SPS and the female sex predominance of anti-amphiphysin positive SPS highlights the atypical presentation of the patient documented in this case report.

Lorish et al. proposed diagnostic criteria for stiff-person syndrome including:

• Stiffness and rigidity in axial muscles

• Progression of stiffness to include proximal limb muscles

• Abnormal axial posture (lumbar hyperlordosis)

• Superimposed episodic spasms precipitated by sudden movement, emotional upsets and unexpected auditory and somaesthetic stimuli (startle phenomenon)

• Absence of brainstem, pyramidal, extrapyramidal, and lower motor neuron (LMN) signs, sphincter and sensory disturbance, and cognitive involvement

• Electromyography findings consistent with continuous motor unit activity in at least one axial muscle that may be abolished with administration of diazepam.¹⁷

In addition, as described above subsequent investigations determined that stiff-person syndrome is associated with antibodies to GAD and amphiphysin (paraneoplastic SPS).

Notably, many of the patient’s symptoms were non-specific. However, an outside provider was able to diagnosis the patient with stiff-person syndrome given a positive amphiphysin antibody titer in the setting of several of the diagnostic criteria proposed by Lorish et al. including stiffness and rigidity in axial muscles, a history of startle phenomenon, and an absence of brainstem, pyramidal, extrapyramidal, and LMN signs, sphincter and sensory disturbance, and cognitive involvement. Subsequent EMG testing was also consistent with stiff person syndrome. To our knowledge, no providers documented abnormal axial posture. As in this patient, the presence of anti-amphiphysin antibodies in a patient with symptoms suggestive of SPS should prompt a thorough oncologic work-up. Interestingly, malignancy was not detected in this patient, despite a positive amphiphysin antibody titer, until three years following the initial onset of symptoms.

As seen by our patient’s initial diagnosis of Lyme disease, the early stages of stiff person syndrome may be challenging to diagnose. The differential diagnosis of stiff person syndrome is broad and may include psychogenic movement disorders, Parkinson’s disease, tetanus, hyperekplexia, axial dystonia, and diseases impacting the spinal cord.

Standard treatment of classic SPS is aimed at symptomatic improvement. Traditionally, the first-line symptomatic therapy for SPS is GABA modulation through benzodiazepine therapy. Patients with an insufficient response or poor tolerance to benzodiazepine therapy may be trialled on GABA agonist therapy through oral baclofen. In patients who continue to have a poor response to benzodiazepine and baclofen therapy, further treatment is aimed at immune modulation via IVIG therapy,^{18 19} plasma exchange²⁰ and rituximab.^{21 22} Additional therapies including sodium valproate,²³ vigabatrin,²⁴ methocarbamol,²⁵ propofol,²⁶ botulinum toxin A²⁷ and tacrolimus²⁸ have been investigated in limited cases but the benefit of these therapies for SPS remains unclear. Glucocorticoids were a treatment option in classic SPS, but have fallen out of favour due to the adverse side effects of high dose glucocorticoid therapy.²⁹ As documented in this report, yoga and meditation may also be effective treatments for SPS symptoms.

In addition to the symptomatic therapies described above, oncological treatment for underlying malignancy is a critical component of anti-amphiphysin positive SPS treatment. Following tumour excision and treatment with glucocorticoids improvement of neurological symptoms has been observed in patients with anti-amphiphysin positive SPS.¹⁴ Interestingly, this patient reported significant improvement in SPS symptoms with cyclophosphamide, a standard component of breast cancer chemotherapy, before a diagnosis of cancer was made.

Management of invasive ductal carcinoma is tailored to the stage of an individual patient’s disease and may involve lumpectomy, mastectomy, chemotherapy, endocrine therapy and radiation. As with the omission of taxane-based chemotherapy in the patient with SPS described in this report, we recommend tailoring chemotherapeutic regimens to minimise adverse outcomes in specific patient conditions.

Patient’s perspective.

My biggest challenge was the uncertainty of knowledge over the origin for my pain and progressing disabilities, which have been advancing for several years. Therefore, when I was diagnosed with breast cancer I finally had a tangible root cause for which standard proven treatments were available. The outlook that my neurological issues might improve after surgery, I was told, made me the most joyful recipient for a positive cancer diagnosis.

The mastectomy was less painful than expected but the drainage management proved itself cumbersome. Subsequent chemotherapy I tolerated well with a 5-day recovery time after each one. Radiation, when entering into the last 10, turned out to be the most painful of the entire process.

Post surgery immediate improvements for stiff-person syndrome and paraneoplastic neurological syndrome were mixed. The pain in the arms and lymph drainage blockages subsided within days. 1 year 3 months after the surgery date, all the other symptoms were still present but have weakened to a point where I no longer require pain medication. Presently, (2 years postoperatively) the improvements continue mostly in the upper body and the least are in the legs and feet.

I am very grateful for the medical people and institutions where I received care. If you ever find yourself without the right answers for a medical condition, consider seeking additional opinions.

Learning points.

• Anti-amphiphysin positive stiff-person syndrome (SPS) is a rare paraneoplastic variant of SPS characterised by painful muscle spasms, progressive musculoskeletal rigidity and underlying malignancy.

• The prolonged diagnostic course highlighted in this case report characterised by episodic improvement with chemotherapeutic agents prior to diagnosis underscores the importance of continued consideration of malignancy as the underlying aetiology of anti-amphiphysin positive SPS even when not evident at the time of symptom onset.

• Once the diagnosis is established, standard oncological therapy and symptomatic treatment of neurological symptoms are the mainstays of treatment. As described in this report, meditation and yoga may also be beneficial in addressing SPS symptoms.