A 68-year-old man presented with a 6-month history of progressive stiffness that started from the bilateral lower limbs, ascending to the body trunk and waist and leading to a fixed deformity. The stiffness was prone to be superimposed by minor tactile stimuli, and considerable time and effort were required for him to be fully relieved to ambulation. There was no significant medical, family, or psychosocial history with the exception of a previous myocardial infarction. Neurologic examination revealed an alert and fully oriented man with restricted upward gaze. Muscle tone was persistently increased in bilateral lower limbs and was elicitable in the upper limbs and abdominal muscles upon tactile stimuli. Tendon reflexes were generally reduced. Postural abnormalities were marked by flexion contracture and difficulty in initiating gait. The distribution and trigger of rigidity were in concordance with classic SPS, and his vertical oculomotor palsy was initially considered as an unusual abnormality occurring in SPS and GAD antibody spectrum disorder-related cerebellar ataxia.

He was admitted with a suspected diagnosis of SPS and underwent relevant examinations. Laboratory tests were largely unremarkable except for inflammatory indicators and thyroid function panels, namely, an elevated erythrocyte sedimentation rate (ESR) of 33 mm/h, a borderline positive result of respiratory syncytial virus (RSV) IgM, and a decreased free thyroxine (FT4) level of 0.39 ng/dL ( Supplementary Table ). A lumbar puncture was performed, revealing cerebrospinal fluid (CSF) cell counts and a protein level of 4×10⁶/L and 68.6 mg/dL, respectively. Despite an increased 24-h intrathecal IgG synthesis rate of 13.55 mg/24 h, the findings of type IV oligoclonal bands and a CSF serum albumin ratio of 9.46×10⁻³ indicated the breakdown of the blood–brain barrier and the absence of intrathecal IgG synthesis. No anti-GAD or anti-amphiphysin antibodies—both known to be pathogenic for SPS—were detected in either serum or CSF. EMG observed paroxysmal motor-unit potential firing of the right rectus abdominis at the resting state, which self-relieved after 4 min without using diazepam ( Figures 1A,B ). Clonazepam 1 mg daily was administered as standard SPS treatment, but no expected improvement in stiffness was observed. These atypical features raised red flags, promoting alternative explanations beside the diagnostic hypothesis of SPS.

Though clonazepam was gradually withdrawn due to the side effects of drowsiness and feebleness, the symptoms persisted and rapidly progressed to somnolence and delirium. The electrolyte result reported a severe hyponatremia with a sodium level of 121 mmol/L. Standard intravenous and oral sodium supplementation was initiated, which proved ineffective in the subsequent 2 days. Further investigations were thus conducted. Brain magnetic resonance imaging (MRI) revealed a homogeneously enhanced pituitary with an empty sella, redirecting an alternative diagnosis to the underlying pituitary pathology ( Figures 1C–E ). A pituitary crisis was suspected based on an abnormal pituitary function panel ( Supplementary Table ), particularly disruption of gonadal function (FSH 0.97 mIU/mL, LH 0.38 mIU/mL, and PRL >204 ng/mL). Given the infection upon admission, the pituitary decompensation was presumably attributed to precipitated inflammatory stress. Meanwhile, the patient’s condition further deteriorated to the extent of developing acute coronary syndrome when the Troponin I level peaked at 4.636 ng/mL and the electrocardiogram showed ST-segment depression in the inferior and extensive anterior leads.

For treatment, acyclovir, ceftriaxone, and intravenous immunoglobulin (10 and 25 g/day for 3 days each) were administered to address potential infection. In addition, intravenous corticosteroid supplement was initiated with hydrocortisone 200 mg/day for 5 days, followed by methylprednisolone 1,000 mg/day for 3 days with a tapering of 500, 240, and 120 mg/day for 1 day each. Conservative strategies, mainly dual antiplatelet and warfarin, were applied for the cardiovascular event. Two days after the addition of hydrocortisone 200 mg/day, there was a dramatic improvement in both consciousness and stiffness, accompanied by normalization of sodium level to 140 mmol/L. Over the following 10 days, the patient’s consciousness gradually returned to normal. Meanwhile, he exhibited significant improvement in stiffness and ambulation without assistance. Neurologic examination revealed an alert man with mild cognitive impairment. Increased muscle tone remained, but tendon reflexes recovered normally in the upper limbs, with a bilateral positive Babinski sign. Plasma sodium level stabilized at 135 mmol/L and Troponin I recovered to 0.009 ng/mL. The patient was subsequently discharged with a prescription of prednisone 60 mg, levothyroxine 25 μg, and bromocriptine 2.5 mg daily.

A pituitary operation was performed 1 month later, which revealed a yellow gelatinous tumor that invaded into the cavernous sinus, wrapping the internal carotid artery and compressing cranial nerve III and VI ( Figures 2A,B ). Post-operational biopsy confirmed the diagnosis of invasive macroprolactinoma ( Figures 2C–F ). PRL returned to physiological ranges 5 days after the total tumor resection. The patient’s clinical manifestations of pyramidal tract signs and contractures, as well as biochemical abnormalities, resolved completely in the 1-year follow-up. Yet, his mild cognitive impairment remained until the end of the follow-up.

A systematic literature review was conducted in PubMed and Google Scholar to identify relevant articles reporting SPS mimics associated with hormone disturbances. The search was performed using the search term [(hypopituitarism) OR (hypoadrenalism) OR (hypocortisolism)] AND [(stiff person syndrome) OR (stiff man syndrome)]. The last literature search was performed on 12 July 2025, with restriction to English-language publications. References of relevant articles were also screened to identify additional reports. Inclusion criteria comprised eligible cases with (i) initial misdiagnosis of SPS and (ii) subsequent confirmation of hypoadrenalism. Exclusion criteria comprised studies (i) other than case reports, (ii) lacking full-text access, or (iii) with insufficient clinical details for data extraction. The screening of titles, abstracts, and full texts was performed by a single investigator (M.Z.).

From each eligible case, data were collected on patient demographics (age, gender, and ethnicity), underlying etiologies, clinical manifestations, laboratory evaluation, imaging findings, EMG features, diagnoses, treatment, and prognosis. The clinical manifestations included musculoskeletal symptoms, their duration and distribution, and response to standard SPS management. Laboratory evaluation focused on plasma sodium level, endocrine panels, and anti-GAD or anti-amphiphysin antibodies detection. Imaging and EMG findings recorded the pituitary region MRI/CT (computed tomography) and motor-unit activity presentations, respectively. Treatment and prognosis data retrieved information on corticosteroid prescription, additional remedies, and therapeutic response.

A total of six previously reported cases of SPS mimic associated with endocrine dysfunction were identified ( Table 1 ) (8–13). Together with our case, seven patients were included in the analysis. The overall median age was 61 years old (range, 42–68), with a median age of 66 years (range, 61–68) in men and 51 years (range, 42–51) in women. Sex distribution was relatively balanced, with a male-to-female ratio of 4:3.

With respect to underlying etiologies, all male patients (n = 4) were diagnosed with hypopituitarism associated with various sellar masses, comprising both benign and aggressive lesions (11–13). The majority of female patients (n = 2) underwent postpartum hemorrhage and developed hypopituitarism secondary to Sheehan’s syndrome, except one diagnosed with isolated ACTH deficiency and primary hypothyroidism (8–10).

Across cases, the most common musculoskeletal features included muscle stiffness and painful spasms, frequently involving the lower limbs and trunk. Precipitations, such as motion and tactile stimuli, were recorded in three of the cases. The duration of symptoms ranged from 2 weeks to 3 years prior to diagnosis. Laboratory data consistently showed endocrinological dysfunction, namely, the disruption of hypothalamic–pituitary–adrenal (n = 7), hypothalamic–pituitary–thyroid (n = 6), and hypothalamic–pituitary–gonad (n = 4) axes. Hyponatremia in four cases was accompanied by ACTH and/or cortisol deficiency. Negative serum anti-GAD (n = 2) or anti-amphiphysin (n = 1) antibodies were found in all available cases. Neuroimaging findings often revealed abnormalities in pituitary (n = 5) or hypothalamus (n = 1) regions, and EMG examinations demonstrated abnormal motor-unit activity (n = 3).

In the three cases that initially applied standard SPS treatment, including sedatives and anti-spasticity drugs, only transient or partial improvement if any response was observed. Subsequent treatment strategies primarily focused on hormone replacement therapy. Hydrocortisone was initiated, either orally or intravenously, at daily doses ranging from 10 to 300 mg in most patients (n = 6). Moreover, prednisolone 5 mg daily was prescribed alternatively in one case as well. In acute adrenal crisis, high-dose intravenous methylprednisolone and immunoglobulin were administered in combination. Concomitant hypothyroidism and hypogonadism were managed with thyroxine (n = 4) and testosterone (n = 1) replacements, respectively, and surgery or radiotherapy was applied in two patients with pituitary tumors. All the treatment received favorable outcomes, with rapid improvements of neuromuscular symptoms within days or weeks.

We reported a patient with SPS mimic who initially experienced chronic progressive stiffness in the lower limbs and trunk, preceding an acute pituitary crisis characterized by severe hyponatremia and likely precipitated by subclinical infection. Combined with the unusual feature for classic SPS (e.g., oculomotor palsy), the clinical picture ultimately redirected the diagnosis to a movement disorder associated with hypopituitarism secondary to a pathologically confirmed prolactinoma.

Together with six published cases, the pooled findings delineate a distinctive subgroup of SPS mimics associated with endocrine dysfunction. The patients were typically middle-aged to elderly, with sex-specific etiologies. The pattern of sellar masses in male patients and obstetric complications in female patients appeared to underlie the approximately decade-earlier onset observed in females. Despite the phenotypic resemblance to SPS, the movement disorders secondary to hypoadrenalism displayed a distinctive triad: ACTH and/or cortisol deficiency (or related hyponatremia), negative anti-GAD (or anti-amphiphysin) antibodies, and limited response to benzodiazepine. These findings underscore the importance of scrutinizing pituitary function and morphology in atypical SPS cases, which may provide critical clues for hypoadrenalism as an alternative and treatable diagnosis.

This study has several limitations. First, the pre-cortisol level from initial presentation was absent in our case, yet the temporal correlation indirectly supported our hypothesis. Given that the low-dose cortisol was administered prior to plasma hormone determination, it is likely that endogenous cortisol level was further lower than measured. Second, some included cases dated to distant years when clinical evaluations were limited, and the selected databases were unable to ensure exhaustive case retrieval. Nevertheless, the majority of the included studies provide solid clinical data supporting such a rare presentation. Future cohort and experimental studies are warranted to clarify the prevalence of endocrine-related SPS mimics, optimize diagnostic and management strategy, and elucidate the mechanisms by which hormonal deficiencies modulate neuromuscular excitability.