Association of Type 1 Stiff-person Syndrome and Insulinoma: a Case Report and Narrative Review

doi:10.21203/rs.3.rs-4704376/v1

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Association of Type 1 Stiff-person Syndrome and Insulinoma: a Case Report and Narrative Review

https://doi.org/10.21203/rs.3.rs-4704376/v1

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Introduction

Stiff-person syndrome (SPS) is a rare neurological disorder that causes progressive muscle rigidity, gait disturbances and functional impairment; type 1 is autoimmune, with postitive anti-GAD antibodies (Ab) while type 2 is paraneoplastic, associated with anti-amphiphysin Ab.

Case presentation

A 41-year-old man with silent medical history presented with stiffness and functional impairment; after numerous rheumatological and neurological investigations he was diagnosed with SPS, with evidence of high titer anti-GAD Ab. After treatment with benzodiazepines was started, the patient began to experience episodes of confusion, which persisted even after reducing the dosage. During one of these episodes, he was admitted to the emergency department and a glucose level of 26 mg/dL was found. Differential diagnosis led to an insulin secreting neuroendocrine tumor of the pancreas, thus a paraneoplastic origin of SPS was hypothesized. However, anti- amphiphysin Ab were negative, anti-GAD were persistently elevated and symptoms only transiently improved after removal of the tumor.

Conclusion

This is the first case, to our knowledge, of association between type 1 SPS and insulinoma, with partial and transient improvement of neurological symptoms after resolution of the associated hypoglycemic syndrome.

SPS

paraneoplastic

neuroendocrine tumor

autoimmune disease

Stiff-person syndrome (SPS) is a central nervous system disorder which was firstly described in 1956. It is characterized by progressive muscle rigidity (usually starting from the trunk and subsequently affecting distal limb muscles) and painful spasms that lead to gait difficulties, frequent falls and a “wooden-man” appearance ¹. SPS has an estimated prevalence of 1–2 cases per million and an incidence of 1 case per million per year, with most patients presenting between the ages of 20 and 50 ². When initially described, little was known about the pathophysiology of the disease, which was thought to be a psychiatric disorder; it is now established that SPS is an autoimmune disease associated with different types of antibodies, even though the pathogenesis is yet to be fully understood ¹. Currently, therapeutic options for SPS include benzodiazepines, levetiracetam or pregabalin, oral/intrathecal baclofen, rituximab or tacrolimus, intravenous immunoglobulins or plasmapheresis ³.

The prognosis is variable and depends on the initial presentation. Unfortunately, however, many patients remain symptomatic, despite the combination of multiple therapies, their quality of life is severely affected and depression is a frequent comorbidity ⁴.

From a pathogenetic point of view, SPS recognizes three different patterns: type 1 (associated with other autoimmune conditions and typically linked to anti-glutamic acid decarboxylase -GAD- antibodies), type 2 (paraneoplastic, mainly associated with anti-amphiphysin antibodies) and type 3 (idiopathic, seronegative) ^3,5 (Fig. 1).

Type 1 is the most common form, with antibodies reacting with the 65 kDa isoform of GAD found in 60–80% of cases ⁶. As already mentioned, SPS may be associated with several autoimmune disorders (e.g., pernicious anemia, vitiligo, celiac disease, myasthenia gravis), including endocrine diseases, such as type 1 diabetes mellitus (T1DM), Hashimoto’s thyroiditis and Graves’ disease ^1,7. In addition, an association with latent autoimmune diabetes of the adult (LADA) has also been described ⁸.

The association with T1DM is the most common, as the two disorders share anti-GAD antibodies; T1DM is in fact found in about 30% of SPS patients, but only 1 in 10.000 patients with T1DM is affected by SPS ⁹. Of note, anti-GAD antibodies are found in both blood and cerebrospinal fluid of SPS patients, but occur only in the blood of T1DM patients ¹. Several theories have been proposed to explain the difference in pathogenicity: it has been suggested that anti-GAD antibodies recognize different epitopes of the same molecule in the two conditions ¹⁰, otherwise the difference could be related to the higher titer of antibodies present in SPS compared at T1DM ¹¹.

SPS type 2 represents less than 10% of cases, usually presenting in women with breast cancer ¹².

The association of SPS and cancer has been known for years and several hematological as well as solid malignancies have been reported, including endocrine tumors ¹³. A recent case report described a patient with atypical carcinoid of the lung and paraneoplastic SPS secondary to anti-amphiphysin antibodies ¹⁴.

To our knowledge, however, the association between SPS and hormonally active pancreatic tumors, including insulin producing neuroendocrine tumor (NET) has never been reported.

We hereby present the case of a 41-year-old man with a GAD-related SPS, who developed an insulinoma one year after SPS diagnosis.

Histopathology

The surgically removed tumor was fixed in 10% buffered formalin for 24 hours and processed for paraffin embedding. Five-micrometer-thick serial paraffin sections were cut, 3 of which were processed by immunohistochemistry using an automated platform (Ventana BenchMark AutoStainer; Ventana Medical Systems, Tucson, USA) with antibodies against chromogranin A (Ventana/Roche, pre-diluted), insulin (Cell Marque, Rocklin USA, pre-diluted), Ki67 (Dako Agilent Technologies, Santa Clara USA, mouse monoclonal, clone MIB-1, dilution 1/100).

The patient is a 41-year-old male with no known allergies and a silent medical history, except for an appendectomy at the age of 20.

In July 2021, after the second dose of the Spikevax vaccine, he began to experience muscle rigidity with functional impairment.

He subsequently underwent a series of rheumatological and neurological investigations (Table 1) that did not yield a definitive diagnosis. From the beginning, the diagnosis proved difficult due to the non-specific nature of the symptoms and the fact that they never fully met the classification/diagnostic criteria of the conditions. Initially, he was diagnosed with myositis, followed by a diagnosis of spondyloarthritis. Treatment for the latter condition included methotrexate, prednisone, celecoxib, and etanercept; however, there was no clinical improvement. The patient discontinued treatment due to episodes of confusion.

Table 1

Rheumatological and neurological investigations underwent by the patient
Exam	Results
ANA screening	1:640 positivity High titer of anti-SSA (Ro60)
Myositis specific antibodies	Anti-OJ (anti-isoleucyl-tRNA synthetase), thay subsequently became udetectable after surgery
Muscle biopsy	CD4 + and CD8 + lymphocyte (interpreted as anti-synthetase antibody myositis)
Four-limb muscle motor evoked potential	Negative
Encephalic MRI and angio-MRI	No significant findings
ANA: antinuclear; SSA/Ro: Sjogren’s syndrome-related antigen A autoantibodies; CD: cluster of differentiation; MRI: magnetic resonance imaging.

Finally, in March 2023, after an electromyography (EMG) control test, which showed a typical pattern with continuous motor unit activity in agonist and antagonist muscles, and the detection of anti-GAD circulating antibodies, a diagnosis of SPS was established based on the diagnostic criteria summarized in Table 2. A treatment with clonazepam at the initial dose of 5 drops (0.5 mg) bid was started with partial improvement of symptoms. When the dosage was increased to 5 drops tid, the patient reported daytime drowsiness and excessive tiredness. An attempt was made to reduce the morning dose, increasing the bedtime one, but the periods of “confusion” and spatial-temporal disorientation persisted (exacerbated by events of intense psycho-physical stress) and the patient had to be admitted to the ER for these symptoms several times.

Table 2

Stiff-person syndrome diagnostic criteria
Major criteria
Stiffness in the axial and limb muscles, prominently in the abdominal and thoracolumbar paraspinal muscles leading to a fixed deformity (hyperlordosis)
Superimposed painful spasms precipitated by unexpected noises, emotional stress, or tactile stimuli
Electromyography confirmation of continuous motor unit activity in agonist and antagonist muscles.
Absence of other neurological disorders or cognitive impairment that could explain the stiffness
Minor criteria
Positive anti-GAD65 (or antiamphiphysin) antibodies in serum, assessed by immunocytochemistry, Western blot or radioimmunoassay
Clinical response to benzodiazepines
GAD: glutamic acid decarboxylase.

In June 2023, the patient was re-admitted to the ER for confusion and disorientation in space and time. Blood exams showed a glucose value of 26 mg/dL with no other relevant findings. The patient was therefore administered two vials of 33% glucose solution (GS) with subsequent infusion of 10% GS at 100 mL/h. Blood glucose was restored to normal values and a regression of symptoms was observed. A cranial CT scan was performed, but no acute ischemic or hemorrhagic lesions were detected. An abdomen ultrasound revealed no anomalies including a normal pancreatic structure and texture. He was then seen by an endocrinologist and hospitalized in the City of Health and Science Hospital of Turin in the suspicion of a hypoglycemic syndrome of unknown origin.

Despite a continuous infusion of 5% GS and frequent fractionated meals, the patient had hypoglycemia symptoms on several occasions; during one such episode, a blood glucose of 58 mg/dL was recorded associated to insulin and c-peptide levels of 4.8 mIU/L and 2.2 mcg/L, respectively.

In the following days, the only regimen that allowed to maintain normal glucose levels was the infusion of 5% GS during the day and 10% GS at night (with mean glucose values of 80 mg/dL).

After careful medical history review, a low fasting blood glucose level was observed in exams from May 2022 (53 mg/dL) and an episode of confusion relieved by the intake of sugars was reported in January 2023, followed by several unexplained similar events in the following months.

Differential diagnosis

The main diagnostic hypotheses at this point included: T1DM onset (as the association between the two diseases is well established and the patient had anti-GAD antibodies), Hirata syndrome (even though the patient denied any use of supplements containing alpha-lipoic acid), insulinoma (as insulin and c-peptide were not suppressed during an episode of moderate hypoglycemia). Therefore, a subsequent biochemical evaluation, comprehensive of a complete panel of autoantibodies (Table 3) was requested and, on this basis, both T1DM and Hirata syndrome were excluded. Severe hypothyroidism and adrenal insufficiency were ruled out, as well.

Table 3

Biochemical evaluations performed during the hospital stay and follow-up
Diagnosis	Parameter	Values at diagnosis	Values at six months
T1DM	Anti-insulin receptor	Negative	Negative
	Anti-pancreatic islet cells (UJDF)	Positive	Positive: 40
	Anti-tyrosine phosphatase	Negative	Negative
	Anti-zinc transporter	Negative	/
	HbA1c (mmol/mol)	17	33
Hyrata syndrome	Anti-insulin	Negative	Negative
SPS	Anti-GAD (U/mL)	Positive: >250	Positive: 1110
	Anti-amphiphysin antibodies	Negative	Negative
Atrophic gastritis	anti-parietal cells	Negative	Negative
	anti-intrinsic factor	Negative	Negative
Celiac disease	anti-endomysium	Negative	Negative
Thyroiditis	anti-TPO (kIU/L)	Positive: 14.9	Negative
	TSH (mIU/L)	1.032	1.522
	fT4 (ng/L)	8	10
Adrenal insufficiency	Morning serum cortisol (mcg/L)	160	224
MEN1	Calcium (mg/dL)	9.6	9.7
	PTH (pg/mL)	14.3	28.8
T1DM: type 1 diabetes mellitus; HbA1c: glycated hemoglobin; SPS: stiff person syndrome; GAD: glutamic acid decarboxylase; TPO: thyroid peroxidase; TSH: thyroid stimulating hormone; fT4: free T4; MEN1: multiple endocrine neoplasia type 1; PTH: parathyroid hormone.

No further autoantibodies emerged from the screening of other possible autoimmune diseases, except for AbTPO and ICA detected at higher titers.

Consequently, on 05/07/2023 a brief fasting test (Table 4) was performed, leading to the diagnosis of endogenous hyperinsulinism. A therapy with diazoxide was started at the dose of 25 mg tid, progressively increased up to 100 mg qid, with maintenance of 10% GS only at night.

Table 4

Brief fasting test, with glucose measurements every hour, which led to endogenous hyperinsulinism diagnosis.
	10:00 am	11:00 am	12:00 pm	13:00 pm
Blood glucose (mg/dL)	44	37	35	30
Insulin (mIU/L)	6.7	5.7	6.2	5.3
C-peptide (µg/L)	2.2	2.0	2.0	2.0

After a negative contrast abdomen and thorax CT on 06/07/2023, an echoendoscopy was performed on 13/07/2023 showing a hypovascularized and heterogeneous tumor measuring 17 x 18 mm in the tail of the pancreas, which was highly suspicious for a neuroendocrine tumor. The fine needle aspiration material confirmed this suspicion in the presence of medium sized neoplastic cells reactive for chromogranin A, consistent with a well differentiated neuroendocrine tumor.

Surgical treatment

On 20/07/2023 the patient underwent a laparoscopic distal pancreatectomy, with no peri-procedural complications. He was then discharged with the indication of continuing daily glucose monitoring, but with no need of a specific endocrinological therapy.

Histopathology examination

a trabecular and solid growth was observed, made of relatively homogeneous round cells producing chromogranin A and insulin, supporting the diagnosis of well-differentiated insulin-producing neuroendocrine pancreatic tumor (Pan-NET) with free resection margins. According to the WHO 2022 classification, the tumor was graded G2 based on a mitotic count of 2 mitoses per 2 square mm and a Ki67 proliferative index of 8% in areas of highest labeling (Fig. 2). The pathological UICC staging (VIII edition) was pT1.

Outcome and follow-up

After surgery, no more hypoglycemic events occurred and glucose monitoring could be discontinued. Biochemical evaluation showed normal glucose, insulin and chromogranin A (33 ng/mL) levels.

From the neurological point of view, the patient gradually re-initiated physical activity and was able to do movements that were previously very difficult due to rigidity such as shoe-lacing and lower limbs flexion on the trunk. He was also able to go on holiday and swim and gradually increase the intensity of the physical activity. The dosage of clonazepam was reduced to 5 drops (0.5 mg) in the morning and 10 (1 mg) at night. Unfortunately, after a few months, the patient reported an exacerbation of symptoms.

Currently, 12 months after surgery, there is no evidence of reoccurrence of the pancreatic lesion nor hypoglycemia episodes, but the patient’s neurological symptoms persist.

To our knowledge, we described the first case of an association between SPS and insulinoma with almost simultaneous occurrence of symptoms related to the two conditions. Moreover, our case is even more peculiar, considering he was simultaneously harboring both high titers of anti-GAD antibodies (suggestive for type 1 SPS) and a possible paraneoplastic syndrome (more common in SPS type 2).

GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Two isoforms of GAD exist: a cytoplasmic, constitutively active form (GAD67) and a synaptic membrane-associated form (GAD65), the former provides a steady production of GABA, the latter supplies pulses of the neurotransmitter when post-synaptic inhibition is needed ¹.

As mentioned above, it seems that patients with SPS have anti-GAD antibodies that recognize the C-terminal part of GAD65, which block the activity of the enzyme by a non-competitive mechanism; however, this effect does not occur in patients with T1DM and anti-GAD65 antibodies ¹⁰. Other authors propose that the difference in pathogenicity is related to the higher titer of anti-GAD antibodies in SPS, rather than differences in epitope recognition ¹¹.

SPS is associated not only with T1DM, but also with other autoimmune diseases, namely endocrinological diseases.

A retrospective study conducted in Taiwan ⁷ examined 14 cases of SPS and their association with autoimmune disorders.

All patients who tested positive for anti-GAD antibodies had classical SPS, in addition, two of them had autoimmune thyroiditis and were positive for anti-TPO antibodies, one had T1DM and one had LADA. Interestingly, the two patients who had an autoimmune form of diabetes, had low titers of anti-GAD antibodies (100–1000 U/mL) when the disease was diagnosed, but the levels rose to > 2000 IU/mL when they developed SPS. This could confirm the hypothesis that higher titers of anti-GAD are needed for SPS to manifest.

Of the six patients who were negative for anti-GAD Ab, none had autoimmune diabetes or thyroiditis; however, one had Sjögren syndrome (ANA positive and anti-Ro antibody positive), one had myasthenia gravis (Ach-R antibody positive), two had neoplasms (1 lung cancer with paraneoplastic syndrome and 1 thymoma).

In addition to T1DM, LADA and autoimmune thyroiditis, 5–10% of patients with SPS also have Graves’ disease, pernicious anemia or vitiligo ⁶. Moreover, SPS is also associated with autoimmune polyglandular syndrome type 1 (APS1) and type 2 (APS2). APS1 includes muco-cutaneous candidiasis, hypoparathyroidism, and Addison’s disease, but is less frequently associated with T1DM, Hashimoto’s thyroiditis, or chronic hepatitis. APS2 consists of Addison’s disease plus either autoimmune thyroiditis or T1DM, and is associated with hypogonadism, pernicious anemia, celiac disease, and primary biliary cirrhosis ¹⁵.

Intriguingly, Yin Lee et al ¹⁶. recently reported a case of SPS induced by exogenous insulin injection in a patient with LADA. He had positive anti-GAD and anti-insulin antibodies and an insulin deficiency, compatible with the diagnosis of LADA. He began to experience rigidity after insulin was introduced, at the point that he discontinued treatment and had poor glycemic control for over 10 years; when insulin was added again, rigidity worsened and a tolerable abdominal rigidity was finally achieved by splitting the administration of basal insulin into two separate injections 12 hours apart.

Our patient did not receive exogenous insulin but was exposed to inappropriately high levels of endogenous insulin for several months.

A stiff-person-like syndrome has also been described in cases of adrenal insufficiency ¹⁷: in such cases it is postulated that the pathophysiology revolves around hyponatremia and glucocorticoid deficiency, which lead to reduced activity of the Na-K-ATPase and eliminate beta-adrenergic stimulation to the Na-K pump. However, it is important to differentiate rigidity induced by SPS or by cortisol deficiency. In the first case, rigidity involves both flexion and extension and limbs are held in extension, in the latter flexion deformities are predominant. In our patient, however, hypocortisolism was excluded as a concomitant cause of the disorder.

Of note, our patient began to experience SPS symptoms after the second dose of the Spikevax vaccine although only the Sars-Cov-2 infection itself has so far been reported in association with SPS. In one case, a patient developed a transient and reversible stiff-person-like syndrome during the viral infection¹⁸, while another patient, who was already affected by stiff-limb-syndrome, experienced a worsening of the syndrome after the infection, with the development of a generalized SPS¹⁹. Of note, several cases of T1DM with positive GAD antibodies triggered or worsened by Covid-19 have been reported, probably due to augmented proinflammatory cytokines and recruitment of CD8 + T cells²⁰.

As previously mentioned, three subtypes of SPS are currently recognized, with type 2 amphiphysin-positive SPS being the paraneoplastic form ^3,5. Recently, the broader term SPS spectrum disorders (SPSSDs) has been introduced in the clinical practice to include a series of diseases with signs and symptoms similar to those of SPS ²¹.

Breast cancer is the most common carcinoma linked to SPSSDs and these patients were found to suffer from other diseases, including autoimmune disorders such as paraneoplastic encephalomyelitis, T1DM, thyroid disease, rheumatoid arthritis and sarcoidosis. The main antigens found in these patients are amphiphysin, followed by GAD65, acetylcholine receptor and glycine receptor (GlyR). Conversely, in lung cancer associated with SPSSDs the most common antigen is GAD65, followed by amphiphysin. In hematological cancers such as lymphoma, on the other hand, GlyR is the most frequently found antigen. SPSSD is also associated with other tumors such as,, pancreatic, colorectal, renal cell, embryonal, ovarian and prostate carcinomas, testicular seminoma, multiple myeloma, glioma, melanoma and liposarcoma ¹³.

In terms of pathogenesis, the GAD antibody inhibits GAD65 to block GABA synthesis, thereby reducing the uptake of newly synthesized GABA in synaptic vesicles and its synaptic release ²². This determines a decreased GABAergic transmission, which leads to neuronal hyperexcitability and is the core pathophysiological mechanisms in SPS ²³.

Amphiphysins are members of the Bin-Amphiphysin-Rvsp (BAR) proteins; amphiphysin I is expressed in mammalian brains and is associated with SPS and breast cancer, while amphiphysin II is associated with cancer progression and myopathies ²⁴. Type I and IIa share a brain-specific domain, while IIb has a skeletal muscle-specific domain with a tumor suppressor that interacts with the c-Myc oncoprotein ²⁵.

Glycine is an inhibitory neurotransmitter, which is crucial for central nervous system development together with its receptor ²⁶. Its biological function is dependent on specific transporters such as GlyT1 (present in glial cells), that also regulates glutamatergic neurotransmission through N-methyl-D-aspartate (NMDA) receptor, affecting brain function and diseases ²⁷. Glial cells modulate synaptic development in white matter via GlyRs ²⁸.

Some reports of neuroendocrine tumors associated with SPS are present in literature, but in these cases a paraneoplastic anti-amphiphysin positive form was present ¹⁴.

The currently reported patient had positive anti-GAD65 autoantibodies and negative anti-amphiphysin ones; although anti-amphiphysin are the most frequently present in paraneoplastic SPS, as described above, different tumors are associated with different autoantigens. Notably, Yohannan et al. ²⁹ also reported a case of a 20-year old patient affected by mediastinal liposarcoma and SPS who harbored the GAD65 autoantibody, but tested negative for anti-amphiphysin; after resection of the primary mass, her overall performance status improved with outpatient physical therapy and she was independent in her daily activities. However, the authors report that she still has some residual ataxia and remains on diazepam. Even in the oncological setting though, the prognosis of SPS is hard to predict. A previous case described a patient who developed SPS during a first relapse of Hodgkin’s disease which completely regressed after chemotherapy treatment; when a second relapse of the hematological disease occurred, however, no signs of SPS were detected, indicating that SPS is a sporadic paraneoplastic manifestation with an unpredictable trend ³⁰. Nevertheless, SPS prognosis is generally unfavorable, with persisting symptoms despite multiple lines of treatment ⁴.

Hence, the clinical evolution of our patient, with a transient marked improvement of symptoms after resection of the tumor, is more likely due to the absence of constant hypoglycemic episodes rather than a resolution of his neurological condition; a role of placebo effect after the surgery, with removal of the apparent cause of disease for the patient, must also be considered.

Our case report has some limitations. Firstly, anti-GlyR autoantibodies, that could also potentially be associated with paraneoplastic SPS, were not determined given the unavailability of the assay in our laboratory. Secondly, a definite cause-effect relationship between SPS and the insulin producing NE tumor cannot be assessed, and whether the patient had a type 1 SPS, a paraneoplastic SPS or an overlapping form of the two cannot be clearly established.

We presented the first case of association between SPS and insulinoma in a patient who had positive anti-GAD and negative anti-amphiphysin antibodies. The onset of neurological symptoms after vaccination and only transient improvement of symptoms after tumor resection probably indicate an autoimmune pathogenesis of the syndrome (SPS type 1). In any case, the overlap of the neurological picture with the neuroglycopenic manifestations made both the differential diagnosis and clinical management challenging. This case well summarizes the complex nature of SPS and the frequent interaction of this syndrome with the endocrine system.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

This is an observational and descriptive study. The Local Ethics Committee has confirmed that no ethical approval is required.

Informed consent

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Funding Sources

This study was not supported by any sponsor or funder.

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Association of Type 1 Stiff-person Syndrome and Insulinoma: a Case Report and Narrative Review

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Introduction

Methods

Histopathology

Case presentation

Differential diagnosis

Surgical treatment

Histopathology examination

Outcome and follow-up

Case discussion and literature review

Conclusions

Declarations

References

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