Stiff Person Syndrome¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Approved
DIAGNOSIS: Stiff Person Syndrome (SPS)
ICD-10: G25.82 (Stiff-man syndrome)
CPT CODES: 85025 (CBC with differential), 80053 (CMP (BMP + LFTs)), 86235 (Anti-GAD65 antibodies (serum)), 82550 (CK (creatine kinase)), 82947 (Blood glucose), 83036 (HbA1c), 84443 (TSH), 84439 (Free T4), 85652 (ESR), 86140 (CRP), 83735 (Magnesium), 84100 (Phosphorus), 83605 (Lactate), 81003 (Urinalysis), 87040 (Blood cultures (x2 sets)), 82607 (Vitamin B12), 86255 (Paraneoplastic antibody panel (Hu, Yo, Ri, CV2/CRMP5, Ma2)), 86376 (Anti-thyroid peroxidase (anti-TPO)), 86800 (Anti-thyroglobulin antibodies), 86340 (Anti-intrinsic factor antibodies), 86337 (Insulin antibodies), 86341 (Islet cell antibodies (ICA)), 86334 (Serum protein electrophoresis (SPEP)), 82784 (Quantitative immunoglobulins (IgG, IgA, IgM)), 87389 (HIV), 80074 (Hepatitis B surface antigen + core antibody), 86480 (QuantiFERON-TB Gold), 70553 (MRI brain with and without gadolinium), 95907-95913 (EMG/NCS (electromyography/nerve conduction studies)), 74178 (CT chest/abdomen/pelvis with contrast), 93000 (ECG (12-lead)), 71046 (Chest X-ray), 77067 (Mammography (females)), 71260 (CT chest with contrast (if not done above)), 78816 (PET/CT (whole body)), 76856 (Pelvic ultrasound (females)), 76870 (Testicular ultrasound (males, young)), 76830 (Transvaginal ultrasound (females)), 88305 (Skin biopsy (punch) for small fiber neuropathy), 77049 (MRI breast (if mammography inconclusive)), 95711 (Video-EEG monitoring (long-term)), 89050 (Opening pressure), 89051 (Cell count with differential (tubes 1 and 4)), 84157 (Protein), 82945 (Glucose with paired serum glucose), 83916 (Oligoclonal bands (CSF AND paired serum)), 83787 (IgG index), 88104 (CSF cytology), 88184 (CSF flow cytometry)
SYNONYMS: Stiff person syndrome, SPS, stiff-man syndrome, Moersch-Woltman syndrome, stiff-limb syndrome, SLS, progressive encephalomyelitis with rigidity and myoclonus, PERM, stiff trunk syndrome, stiff person spectrum disorder, SPSD, anti-GAD stiffness syndrome, autoimmune rigidity syndrome, GAD antibody-associated stiffness, stiff body syndrome
SCOPE: Diagnostic workup and management of suspected or confirmed Stiff Person Syndrome and its spectrum disorders (classic SPS, stiff-limb syndrome, PERM) across all care settings. Covers initial evaluation, antibody testing (anti-GAD65, anti-amphiphysin, anti-DPPX, anti-glycine receptor), EMG findings, first-line symptomatic therapy (benzodiazepines, baclofen), immunotherapy (IVIg, rituximab, plasmapheresis), and management of acute exacerbations including status spasticus. For isolated cerebellar ataxia with anti-GAD antibodies or autoimmune epilepsy with anti-GAD antibodies, use respective templates. For tetanus or functional neurological disorder evaluation, use respective templates.
DEFINITIONS: - Classic Stiff Person Syndrome: Progressive rigidity and episodic spasms affecting primarily axial and proximal limb muscles with continuous motor unit activity on EMG and positive anti-GAD65 antibodies (typically >2000 IU/mL) - Stiff-Limb Syndrome (SLS): Variant with rigidity and spasms predominantly affecting one or more limbs, often asymmetric; anti-GAD65 may be positive - Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM): Most severe variant with brainstem and spinal cord involvement; rigidity, myoclonus, autonomic dysfunction, encephalopathy; associated with anti-glycine receptor (GlyR) antibodies or anti-DPPX antibodies - Paraneoplastic SPS: SPS associated with anti-amphiphysin antibodies; most commonly breast cancer, lung cancer, or thymoma - Status Spasticus: Severe, prolonged, unrelenting spasms with potential for respiratory compromise, rhabdomyolysis, and autonomic instability; neurological emergency
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
═══════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════
1. LABORATORY WORKUP¶
1A. Essential/Core Labs¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| CBC with differential (CPT 85025) | Baseline; infection screen; pre-immunotherapy assessment | Normal | STAT | STAT | ROUTINE | STAT |
| CMP (BMP + LFTs) (CPT 80053) | Metabolic screen; renal/hepatic function; pre-immunotherapy baseline | Normal | STAT | STAT | ROUTINE | STAT |
| Anti-GAD65 antibodies (serum) (CPT 86235) | Primary diagnostic antibody; present in ~80% of classic SPS; titers >2000 IU/mL highly suggestive of SPS (vs. lower titers in T1DM, cerebellar ataxia) | Positive, high titer (>2000 IU/mL) | URGENT | STAT | ROUTINE | URGENT |
| CK (creatine kinase) (CPT 82550) | Rhabdomyolysis from severe spasms; elevated during acute exacerbations | Normal or elevated during spasms | STAT | STAT | ROUTINE | STAT |
| Blood glucose (CPT 82947) | Screen for concurrent type 1 diabetes mellitus (30-60% comorbidity with SPS); pre-treatment baseline | Normal or elevated (if T1DM) | STAT | STAT | ROUTINE | STAT |
| HbA1c (CPT 83036) | Type 1 diabetes mellitus screening and monitoring (common autoimmune comorbidity) | <5.7% (normal); >6.5% suggests DM | - | ROUTINE | ROUTINE | - |
| TSH (CPT 84443) | Autoimmune thyroiditis screening (common comorbidity) | Normal | URGENT | ROUTINE | ROUTINE | URGENT |
| Free T4 (CPT 84439) | Thyroid function if TSH abnormal | Normal | URGENT | ROUTINE | ROUTINE | URGENT |
| ESR (CPT 85652) | Inflammatory marker; baseline | Normal to mildly elevated | URGENT | ROUTINE | ROUTINE | URGENT |
| CRP (CPT 86140) | Inflammatory marker; infection screen | Normal | URGENT | ROUTINE | ROUTINE | URGENT |
| Magnesium (CPT 83735) | Hypomagnesemia can exacerbate spasms; seizure threshold | Normal (1.8-2.4 mg/dL) | STAT | STAT | ROUTINE | STAT |
| Calcium (total and ionized) (CPT 82310+82330) | Hypocalcemia exacerbates spasms; metabolic screen | Normal | STAT | STAT | ROUTINE | STAT |
| Phosphorus (CPT 84100) | Metabolic screen | Normal | STAT | STAT | ROUTINE | STAT |
| Lactate (CPT 83605) | Lactic acidosis from prolonged severe spasms | Normal (<2 mmol/L) | STAT | STAT | - | STAT |
| PT/INR, aPTT (CPT 85610+85730) | Coagulation status pre-LP | Normal | STAT | STAT | - | STAT |
| Urinalysis (CPT 81003) | Myoglobinuria screen if rhabdomyolysis suspected; infection screen | Negative for myoglobin | STAT | STAT | ROUTINE | STAT |
| Blood cultures (x2 sets) (CPT 87040) | Rule out infection (especially tetanus differential; pre-immunosuppression) | No growth | STAT | STAT | - | STAT |
| Vitamin B12 (CPT 82607) | Myelopathy/neuropathy differential | Normal (>300 pg/mL) | - | ROUTINE | ROUTINE | - |
1B. Extended Workup (Second-line)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Anti-amphiphysin antibodies (serum) (CPT 86235) | Paraneoplastic SPS marker; associated with breast cancer, lung cancer, thymoma; present in ~5% of SPS | Negative (positive indicates paraneoplastic variant) | - | URGENT | ROUTINE | URGENT |
| Anti-glycine receptor (GlyR) antibodies (serum) (CPT 86235) | PERM variant marker; associated with brainstem involvement, myoclonus, autonomic dysfunction | Negative (positive suggests PERM variant) | - | URGENT | ROUTINE | URGENT |
| Anti-DPPX antibodies (serum) (CPT 86235) | PERM variant with hyperexcitability, GI dysmotility, cognitive changes | Negative (positive suggests PERM) | - | URGENT | ROUTINE | URGENT |
| Anti-GABA-A receptor antibodies (CPT 86235) | Associated with SPS spectrum; seizures and encephalopathy | Negative | - | ROUTINE | ROUTINE | - |
| Anti-GABA-B receptor antibodies (CPT 86235) | Associated with SPS spectrum; seizures; paraneoplastic | Negative | - | ROUTINE | ROUTINE | - |
| Paraneoplastic antibody panel (Hu, Yo, Ri, CV2/CRMP5, Ma2) (CPT 86255) | Comprehensive paraneoplastic screen; amphiphysin-positive SPS is paraneoplastic | Negative | - | URGENT | ROUTINE | URGENT |
| Anti-thyroid peroxidase (anti-TPO) (CPT 86376) | Autoimmune thyroiditis comorbidity screen | Negative | - | ROUTINE | ROUTINE | - |
| Anti-thyroglobulin antibodies (CPT 86800) | Autoimmune thyroiditis comorbidity screen | Negative | - | ROUTINE | ROUTINE | - |
| Anti-parietal cell antibodies (CPT 86255) | Pernicious anemia comorbidity screen (autoimmune gastritis) | Negative | - | ROUTINE | ROUTINE | - |
| Anti-intrinsic factor antibodies (CPT 86340) | Pernicious anemia comorbidity screen | Negative | - | ROUTINE | ROUTINE | - |
| Insulin antibodies (CPT 86337) | Type 1 diabetes autoimmune panel | Negative | - | ROUTINE | ROUTINE | - |
| Islet cell antibodies (ICA) (CPT 86341) | Type 1 diabetes autoimmune panel | Negative | - | ROUTINE | ROUTINE | - |
| ANA (CPT 86235) | Autoimmune comorbidity screen (lupus, Sjogren) | Negative or low titer | - | ROUTINE | ROUTINE | - |
| Serum protein electrophoresis (SPEP) (CPT 86334) | Monoclonal gammopathy screen; lymphoma differential | Normal pattern | - | ROUTINE | ROUTINE | - |
| Quantitative immunoglobulins (IgG, IgA, IgM) (CPT 82784) | Baseline before IVIg; hypogammaglobulinemia screen before rituximab | Normal | - | ROUTINE | ROUTINE | - |
| HIV (CPT 87389) | Immunocompromised screen | Negative | - | ROUTINE | ROUTINE | - |
| Hepatitis B surface antigen + core antibody (CPT 80074) | Reactivation risk before rituximab or immunosuppression | Negative | - | ROUTINE | ROUTINE | - |
| Hepatitis C antibody (CPT 80074) | Screen before immunosuppression | Negative | - | ROUTINE | ROUTINE | - |
| QuantiFERON-TB Gold (CPT 86480) | TB exclusion before immunosuppression | Negative | - | ROUTINE | ROUTINE | - |
1C. Rare/Specialized (Refractory or Atypical)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Anti-GAD65 antibodies (paired CSF and serum with index) (CPT 86235) | Intrathecal anti-GAD production; CSF anti-GAD supports diagnosis; serum may be negative in rare cases with positive CSF | CSF anti-GAD positive; intrathecal synthesis | - | EXT | EXT | - |
| Anti-RIG1 (CASPR2) antibodies (CPT 86235) | Neuromyotonia/Morvan syndrome differential; overlaps with SPS spectrum | Negative | - | EXT | EXT | - |
| Anti-LGI1 antibodies (CPT 86235) | Autoimmune encephalitis differential with seizures and movement disorder | Negative | - | EXT | EXT | - |
| Genetic testing for hereditary hyperekplexia (GLRA1, GLRB, SLC6A5) | Hereditary hyperekplexia differential in early-onset cases | Negative | - | - | EXT | - |
| Stiff person syndrome-specific autoantibody panel (comprehensive) | Commercial panels including GAD65, amphiphysin, DPPX, GlyR, GABA-A, GABA-B | Identifies specific antibody profile | - | EXT | EXT | - |
| Serum free light chains (kappa/lambda) | Monoclonal gammopathy and lymphoproliferative disorder screen | Normal ratio | - | EXT | EXT | - |
| Catecholamines (plasma) and metanephrines | Pheochromocytoma if paroxysmal hypertension with spasms (rare differential) | Normal | - | EXT | EXT | - |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI brain with and without gadolinium (CPT 70553) | Within 24-48h | Typically NORMAL in classic SPS (important negative finding); may show cerebellar atrophy if anti-GAD cerebellar involvement; rule out structural lesions, MS, myelopathy | GFR <30; gadolinium allergy; pacemaker | URGENT | URGENT | ROUTINE | URGENT |
| MRI spine (cervical and thoracic) with and without gadolinium (CPT 72156+72157) | Within 24-48h | Typically NORMAL in classic SPS; rule out myelopathy (compressive, inflammatory, vascular); may show cord signal in PERM variant | GFR <30; gadolinium allergy | URGENT | URGENT | ROUTINE | URGENT |
| EMG/NCS (electromyography/nerve conduction studies) (CPT 95907-95913) | Within 1-7 days | Continuous motor unit activity (CMUA) at rest in agonist and antagonist muscles simultaneously; no voluntary suppression; involuntary co-contraction pattern; motor units normal morphology | Anticoagulation (relative for needle EMG) | - | URGENT | ROUTINE | - |
| CT chest/abdomen/pelvis with contrast (CPT 74178) | Within 1-2 weeks | Malignancy screen (breast, lung, thymoma, lymphoma); especially if anti-amphiphysin positive | Contrast allergy; renal insufficiency | - | URGENT | ROUTINE | URGENT |
| ECG (12-lead) (CPT 93000) | Immediate | Baseline rhythm; QTc assessment; autonomic dysfunction | None | STAT | STAT | ROUTINE | STAT |
| Chest X-ray (CPT 71046) | Immediate | Pulmonary pathology screen; malignancy screen | Pregnancy (relative) | STAT | STAT | ROUTINE | STAT |
2B. Extended¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Mammography (females) (CPT 77067) | Within 2-4 weeks | Breast cancer screening (paraneoplastic SPS, especially anti-amphiphysin) | Breast implants (relative) | - | ROUTINE | ROUTINE | - |
| CT chest with contrast (if not done above) (CPT 71260) | Within 1-2 weeks | Thymoma; lung cancer; mediastinal lymphadenopathy | Contrast allergy; renal insufficiency | - | ROUTINE | ROUTINE | - |
| PET/CT (whole body) (CPT 78816) | Within 2-4 weeks | Occult malignancy (if paraneoplastic SPS suspected or anti-amphiphysin positive); breast, lung, thymoma, lymphoma | Uncontrolled diabetes; pregnancy | - | ROUTINE | ROUTINE | - |
| Pelvic ultrasound (females) (CPT 76856) | Within 2-4 weeks | Ovarian cancer screen (paraneoplastic) | None significant | - | ROUTINE | ROUTINE | - |
| Testicular ultrasound (males, young) (CPT 76870) | Within 2-4 weeks | Testicular cancer screen if paraneoplastic suspected | None significant | - | ROUTINE | ROUTINE | - |
| Transvaginal ultrasound (females) (CPT 76830) | Within 2-4 weeks | Ovarian pathology; paraneoplastic screen | Patient refusal | - | ROUTINE | ROUTINE | - |
| EEG (routine or continuous) (CPT 95816 or 95711) | Within 1-7 days | Rule out epileptic origin of spasms; PERM variant may show encephalopathic changes; differentiate from epileptic myoclonus | None significant | URGENT | URGENT | ROUTINE | URGENT |
| Pulmonary function tests (PFTs) with inspiratory/expiratory pressures (CPT 94010+94060) | Within 1-2 weeks | Respiratory muscle function; restrictive pattern from chest wall rigidity; assess ventilatory capacity | Unable to cooperate | - | ROUTINE | ROUTINE | URGENT |
| Skin biopsy (punch) for small fiber neuropathy (CPT 88305) | Within 2-4 weeks | Intraepidermal nerve fiber density; SPS can coexist with small fiber neuropathy | Coagulopathy; skin infection at site | - | - | ROUTINE | - |
2C. Rare/Specialized¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| FDG-PET brain | If atypical presentation | Cerebellar or brainstem hypermetabolism (PERM); cortical dysfunction | Uncontrolled diabetes | - | EXT | EXT | - |
| MRI breast (if mammography inconclusive) (CPT 77049) | If paraneoplastic suspected | Occult breast cancer | Claustrophobia; breast implants (relative) | - | EXT | EXT | - |
| Video-EEG monitoring (long-term) (CPT 95711) | If diagnosis uncertain | Distinguish epileptic vs. non-epileptic spasms; characterize movement phenomenology | None significant | - | EXT | EXT | - |
| Somatosensory evoked potentials (SSEPs) (CPT 95925+95926) | If PERM suspected | Central sensory pathway assessment; spinal cord involvement | None significant | - | EXT | EXT | - |
LUMBAR PUNCTURE¶
Indication: Supports diagnosis of SPS via CSF anti-GAD65 antibodies and intrathecal synthesis; rules out infectious/inflammatory mimics; essential when serum antibodies equivocal or negative but clinical suspicion remains high
Timing: URGENT in ED/hospital setting if diagnosis uncertain; ROUTINE for outpatient diagnostic workup. Perform after CT/MRI to rule out mass lesion
Volume Required: 10-15 mL (standard diagnostic volume; sufficient for antibody studies and basic CSF)
| Study | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Opening pressure (CPT 89050) | Assess for elevated ICP; typically normal in SPS | 10-20 cm H2O (normal) | URGENT | ROUTINE | ROUTINE | - |
| Cell count with differential (tubes 1 and 4) (CPT 89051) | Rule out infection and inflammation; usually normal or mild pleocytosis in SPS | WBC <5 (usually normal); RBC 0 | STAT | STAT | ROUTINE | STAT |
| Protein (CPT 84157) | May be mildly elevated; rule out infectious meningitis | Normal to mildly elevated (15-60 mg/dL) | STAT | STAT | ROUTINE | STAT |
| Glucose with paired serum glucose (CPT 82945) | Rule out infectious meningitis; typically normal in SPS | Normal (>60% of serum) | STAT | STAT | ROUTINE | STAT |
| CSF anti-GAD65 antibodies (CPT 86235) | Intrathecal anti-GAD synthesis; may be positive even when serum is negative; calculate CSF/serum ratio to confirm intrathecal production | Positive (supports diagnosis); calculate index | URGENT | URGENT | ROUTINE | URGENT |
| Oligoclonal bands (CSF AND paired serum) (CPT 83916) | Intrathecal IgG synthesis; may show CSF-specific bands in SPS; helps distinguish from MS | May show CSF-specific bands | URGENT | ROUTINE | ROUTINE | - |
| IgG index (CPT 83787) | Intrathecal antibody synthesis | May be elevated | URGENT | ROUTINE | ROUTINE | - |
| Gram stain and bacterial culture (CPT 87205+87070) | Rule out bacterial meningitis (tetanus differential) | No organisms | STAT | STAT | ROUTINE | STAT |
| CSF cytology (CPT 88104) | Malignancy exclusion if paraneoplastic suspected | Negative for malignant cells | - | ROUTINE | ROUTINE | - |
| CSF flow cytometry (CPT 88184) | CNS lymphoma exclusion if atypical presentation | Normal | - | ROUTINE | ROUTINE | - |
Special Handling: CSF anti-GAD65 requires paired serum sample drawn simultaneously for index calculation. Store extra CSF (frozen at -20C) for future testing. Process CSF antibodies promptly.
Contraindications: Elevated ICP without imaging (get CT/MRI first); coagulopathy (INR >1.5, platelets <50K); skin infection at LP site; severe spasms preventing safe positioning (may require sedation)
3. TREATMENT¶
3A. Acute/Emergent¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Diazepam | IV | Acute severe spasms; status spasticus; first-line benzodiazepine for SPS | 5-10 mg :: IV :: PRN q5-10 min :: 5-10 mg IV push over 2-5 minutes; may repeat q5-10 min PRN; max 30 mg in first hour; then transition to scheduled dosing; typical maintenance 10-30 mg PO TID-QID | Respiratory depression without ventilator support; acute narrow-angle glaucoma; severe hepatic insufficiency; myasthenia gravis | Respiratory rate; SpO2; sedation level; BP; airway patency; have flumazenil available | STAT | STAT | - | STAT |
| Lorazepam | IV | Acute spasms; alternative to diazepam if IV diazepam unavailable; status spasticus | 2-4 mg :: IV :: PRN q5-10 min :: 2-4 mg IV push over 2 minutes; may repeat q5-10 min; max 8 mg in first hour; less lipophilic than diazepam (shorter CNS duration) | Respiratory depression without ventilator support; acute narrow-angle glaucoma; severe hepatic insufficiency | Respiratory rate; SpO2; sedation level; BP; airway patency | STAT | STAT | - | STAT |
| Midazolam | IV | Status spasticus requiring continuous infusion; ICU setting | 0.05 mg/kg/hr :: IV :: continuous infusion :: 0.5-1 mg IV bolus, then 0.05-0.2 mg/kg/hr continuous infusion; titrate to spasm control; taper gradually over days once spasms controlled | Respiratory depression (requires mechanical ventilation for continuous infusion); acute narrow-angle glaucoma | Continuous SpO2; respiratory rate; BP; sedation level (RASS); ventilator settings | - | - | - | STAT |
| Propofol | IV | Refractory status spasticus not responding to benzodiazepines; ICU with mechanical ventilation | 20 mcg/kg/min :: IV :: continuous infusion :: 0.5-1 mg/kg IV bolus, then 20-50 mcg/kg/min infusion; titrate to spasm suppression; max 80 mcg/kg/min; avoid >48 hours at high doses | Propofol allergy (egg/soy); propofol infusion syndrome risk >48h; hemodynamic instability | Triglycerides q24h; CK; metabolic panel; lactate; propofol infusion syndrome (fever, rhabdo, metabolic acidosis, cardiac failure); hemodynamics | - | - | - | STAT |
| IV crystalloid (normal saline or lactated Ringer) | IV | Rhabdomyolysis prevention and treatment during severe spasms | 250 mL/hr :: IV :: continuous :: 1-2 L bolus then 150-250 mL/hr; target urine output >200 mL/hr if CK >5000; add sodium bicarbonate 150 mEq/L NS if myoglobinuria | Heart failure; volume overload | I/O; CK q6h; BMP q6-12h; urine myoglobin; urine output | STAT | STAT | - | STAT |
| Dantrolene | IV | Refractory spasms with hyperthermia or malignant hyperthermia-like presentation during severe SPS crisis | 1-2.5 mg/kg :: IV :: PRN q5-10 min :: 1-2.5 mg/kg IV push; may repeat q5-10 min; max 10 mg/kg; transition to PO 25-100 mg QID when stabilized | Hepatic disease; active hepatitis | LFTs; hepatotoxicity (BLACK BOX); CK; temperature | - | URGENT | - | STAT |
Note: Benzodiazepines are the cornerstone of acute SPS management. Diazepam is preferred over lorazepam for SPS because of its longer duration, active metabolite (desmethyldiazepam), and greater efficacy for muscle relaxation. SPS patients often require much higher benzodiazepine doses than typical use and develop tolerance more slowly than expected. Status spasticus is a neurological emergency requiring ICU admission, aggressive benzodiazepine dosing, and consideration of propofol/midazolam infusion with mechanical ventilation.
3B. Symptomatic Treatments¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Diazepam | PO | First-line symptomatic therapy for rigidity and spasms in SPS; GABAergic mechanism addresses pathophysiology | 5 mg :: PO :: TID :: Start 5 mg PO TID; titrate by 5 mg/dose every 3-5 days as tolerated; typical effective dose 20-60 mg/day in divided doses; some patients require up to 100+ mg/day; max limited by sedation | Respiratory depression; acute narrow-angle glaucoma; severe hepatic insufficiency; myasthenia gravis; severe OSA without CPAP | Sedation; respiratory status; falls; cognitive function; tolerance; dependence (do NOT abruptly discontinue) | URGENT | URGENT | ROUTINE | URGENT |
| Baclofen | PO | Adjunctive to benzodiazepines for rigidity and spasms; GABA-B agonist | 5 mg :: PO :: TID :: Start 5 mg PO TID; increase by 5 mg/dose every 3-5 days; target 40-80 mg/day in divided doses; max 80 mg/day (higher doses off-label with close monitoring) | Renal impairment (reduce dose); abrupt withdrawal causes seizures and hallucinations | Sedation; dizziness; weakness; renal function; do NOT discontinue abruptly (withdrawal seizures, hallucinations, autonomic instability) | URGENT | URGENT | ROUTINE | URGENT |
| Gabapentin | PO | Adjunctive therapy for rigidity, spasms, and neuropathic pain; anticonvulsant with GABA-modulating properties | 300 mg :: PO :: qHS :: Start 300 mg qHS; titrate by 300 mg q1-3d; target 900-1800 mg TID; max 3600 mg/day | Renal impairment (adjust dose per CrCl) | Sedation; dizziness; peripheral edema; renal function | - | ROUTINE | ROUTINE | - |
| Pregabalin | PO | Adjunctive therapy for rigidity, spasms, and neuropathic pain; alternative to gabapentin | 75 mg :: PO :: BID :: Start 75 mg BID; may increase q1wk; target 150-300 mg BID; max 600 mg/day | Renal impairment (adjust dose); Class V controlled substance | Sedation; weight gain; peripheral edema; dizziness; renal function | - | ROUTINE | ROUTINE | - |
| Tizanidine | PO | Adjunctive therapy for rigidity and spasms; alpha-2 adrenergic agonist muscle relaxant | 2 mg :: PO :: TID :: Start 2 mg PO TID; increase by 2-4 mg q3-7d; max 36 mg/day divided TID; take consistently with or without food | Concurrent fluvoxamine or ciprofloxacin (CYP1A2 inhibitors); hepatic impairment | LFTs at baseline, 1, 3, 6 months, then periodically; BP (hypotension); sedation; dry mouth | - | ROUTINE | ROUTINE | - |
| Clonazepam | PO | Adjunctive benzodiazepine for myoclonus (especially PERM variant); nocturnal spasms | 0.5 mg :: PO :: BID :: Start 0.5 mg PO BID; increase by 0.5 mg q3-5d; max 6 mg/day; useful for myoclonus in PERM variant | Respiratory depression; severe hepatic disease; acute narrow-angle glaucoma | Sedation; ataxia; cognitive impairment; respiratory status; do NOT discontinue abruptly | - | ROUTINE | ROUTINE | - |
| Levetiracetam | PO | Myoclonus treatment (especially PERM variant); anti-seizure prophylaxis if cortical involvement | 500 mg :: PO :: BID :: Start 500 mg PO BID; increase by 500 mg/day q1-2wk; max 3000 mg/day | Renal impairment (adjust dose per CrCl) | Behavioral changes (rage, irritability); suicidality; renal function | URGENT | URGENT | ROUTINE | URGENT |
| Duloxetine | PO | Comorbid neuropathic pain; depression and anxiety (common in SPS) | 30 mg :: PO :: daily :: Start 30 mg PO daily x 1 week; increase to 60 mg daily; max 120 mg/day | Severe hepatic impairment; concurrent MAOIs; uncontrolled narrow-angle glaucoma | BP; hepatic function; serotonin syndrome risk; suicidality monitoring | - | ROUTINE | ROUTINE | - |
| Sertraline | PO | Anxiety and depression comorbidity management; high prevalence in SPS patients | 50 mg :: PO :: daily :: Start 50 mg PO daily; increase by 25-50 mg q1-2wk; max 200 mg/day | Concurrent MAOIs; concurrent pimozide | Suicidality monitoring; serotonin syndrome risk; hyponatremia (SIADH) in elderly | - | ROUTINE | ROUTINE | - |
Note: Diazepam is the cornerstone of symptomatic SPS management and should be tried FIRST. SPS patients often tolerate very high benzodiazepine doses (60-100+ mg/day of diazepam) without excessive sedation due to the underlying GABAergic deficit. Abrupt benzodiazepine withdrawal in SPS can trigger life-threatening status spasticus. Baclofen is the most commonly used adjunct. Gabapentin/pregabalin provide additional benefit, especially for pain.
3C. Second-line/Refractory¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| IVIg (intravenous immunoglobulin) | IV | First-line immunotherapy for SPS; Class I evidence (Dalakas 2001 NEJM RCT); reduces stiffness and improves function | 0.4 g/kg/day :: IV :: daily x 5 days :: 0.4 g/kg/day IV for 5 days (total 2 g/kg); infuse initial rate 0.5 mL/kg/hr, increase q30min by 0.5 mL/kg/hr to max 4 mL/kg/hr; premedicate with acetaminophen and diphenhydramine; repeat every 4-6 weeks for maintenance | IgA deficiency (anaphylaxis risk -- check IgA level); renal insufficiency (use sucrose-free); hypercoagulable states (thrombosis risk) | Renal function (BUN/Cr before each cycle); CBC; vital signs during infusion; headache (aseptic meningitis); DVT/PE risk; hemolysis (DAT, LDH, haptoglobin); IgA level before first infusion | - | URGENT | ROUTINE | URGENT |
| Plasmapheresis (PLEX) | IV | Acute severe SPS or status spasticus not responding to benzodiazepines and IVIg; removes pathogenic antibodies | 1-1.5 plasma volumes :: IV :: q48h x 5 exchanges :: 5 exchanges over 10-14 days (every other day); 1-1.5 plasma volume exchanges per session; albumin replacement (NOT FFP unless coagulopathy); central venous catheter required | Active sepsis; hemodynamic instability; heparin allergy (if used); unable to establish vascular access | BP and vitals during sessions; calcium (citrate-induced hypocalcemia); fibrinogen; coagulation studies; electrolytes; CBC; line infections | - | URGENT | - | STAT |
| Intrathecal baclofen (ITB pump) | IT | Refractory rigidity and spasms not controlled by maximal oral medications; severe functional impairment | 50-100 mcg :: IT :: trial dose :: Trial: 50-100 mcg intrathecal bolus; if positive response, implant programmable pump; typical maintenance 100-800 mcg/day continuous infusion; titrate over weeks | Active infection; coagulopathy; CSF obstruction; patient unable to return for pump refills | Pump function and refill schedule; withdrawal symptoms if pump malfunction (medical emergency -- similar to status spasticus); CSF leak; infection; catheter complications | - | EXT | ROUTINE | - |
| Botulinum toxin A (onabotulinumtoxinA) | IM | Focal refractory rigidity and spasms; specific muscle group targeting | 50-200 units :: IM :: q12 weeks :: Dose varies by muscle group; typical 50-200 units per large muscle (e.g., paraspinal); EMG/ultrasound-guided injection; repeat q12 weeks; onset 3-7 days, peak 2-4 weeks | Systemic neuromuscular disease (relative); infection at injection site; known antibodies to botulinum toxin | Weakness at injection site; dysphagia (if cervical muscles); distant spread effects; antibody development with repeated use | - | ROUTINE | ROUTINE | - |
Note: IVIg has the strongest evidence for SPS treatment (Class I, Dalakas 2001). Response is typically seen within 1-4 weeks and most patients require ongoing maintenance infusions every 4-6 weeks. PLEX is used for acute flares or status spasticus as a bridging therapy. Intrathecal baclofen should be considered when oral medications are insufficient or cause intolerable side effects.
3D. Disease-Modifying / Immunotherapy (Long-term)¶
| Treatment | Route | Indication | Dosing | Pre-Treatment Requirements | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|---|
| Rituximab | IV | Second-line immunotherapy for SPS; B-cell depletion reduces anti-GAD production; used when IVIg insufficient or for IVIg-sparing | 1000 mg :: IV :: q2wk x 2 doses :: 1000 mg IV x 2 doses (day 0 and day 14); repeat based on CD19/CD20 repopulation or clinical relapse (typically q6 months); premedicate with methylprednisolone 100 mg IV, acetaminophen 650 mg, diphenhydramine 50 mg | Hepatitis B serology; CBC, CMP; quantitative immunoglobulins (IgG, IgA, IgM); JCV antibody (PML risk); TB screening (QuantiFERON); pregnancy test; vaccination update (before initiating) | Active hepatitis B; severe active infection; live vaccines within 4 weeks; severe hypogammaglobulinemia (IgG <300) | Hepatitis B surveillance; CBC q2-4 weeks initially; immunoglobulin levels q3-6 months; CD19/CD20 B-cell counts q3 months; infusion reactions (slow rate if reaction); PML surveillance; infection monitoring | - | URGENT | ROUTINE | URGENT |
| Mycophenolate mofetil | PO | Steroid-sparing immunosuppression; adjunctive to IVIg or rituximab | 500 mg :: PO :: BID :: Start 500 mg PO BID; increase by 500 mg every 2 weeks; target 1000-1500 mg BID (2000-3000 mg/day total); onset of effect 2-3 months | CBC, CMP, LFTs; pregnancy test; hepatitis B/C serology; TB screen | Pregnancy (Category D -- teratogenic); active infection; concurrent live vaccines | CBC q2 weeks x 3 months then monthly; LFTs; GI symptoms (diarrhea, nausea); infection surveillance; pregnancy prevention (two forms of contraception) | - | ROUTINE | ROUTINE | - |
| Azathioprine | PO | Steroid-sparing agent; adjunctive immunotherapy for SPS | 50 mg :: PO :: daily :: Start 50 mg PO daily; increase by 50 mg every 2 weeks; target 2-3 mg/kg/day; onset of action 3-6 months | TPMT genotype/activity level; CBC, CMP, LFTs; hepatitis B/C; TB screen | TPMT deficiency (myelosuppression risk); concurrent allopurinol (reduce dose 75%); pregnancy (relative) | TPMT genotype before starting; CBC q2 weeks x 2 months then monthly; LFTs monthly; amylase if abdominal pain (pancreatitis) | - | ROUTINE | ROUTINE | - |
| Prednisone | PO | Adjunctive immunosuppression; short-term during acute flares; bridge while waiting for IVIg/rituximab effect; less effective as monotherapy for SPS | 0.5-1 mg/kg/day :: PO :: daily :: 0.5-1 mg/kg/day (max 60 mg); taper by 10 mg every 2 weeks to 20 mg, then by 5 mg every 2-4 weeks; attempt to discontinue or reach lowest effective dose; avoid prolonged use (less effective for SPS than for other autoimmune conditions) | Active infection; uncontrolled diabetes; avascular necrosis; psychosis from steroids; PUD | Glucose; BP; weight; mood; bone density (DEXA if >3 months); ophthalmology (cataracts, glaucoma) | - | ROUTINE | ROUTINE | - | |
| Cyclophosphamide | IV | Severe refractory SPS failing IVIg, rituximab, and other agents; last resort | 750 mg/m2 :: IV :: monthly x 6 cycles :: 750 mg/m2 IV monthly for 6 cycles; pre-hydrate with 1L NS; administer with MESNA for uroprotection; adjust for renal function | CBC, CMP, UA before each cycle; pregnancy test; fertility counseling; hepatitis B/C; TB screen | Pregnancy (Category D); active infection; bone marrow failure; bladder outlet obstruction | CBC weekly x 4 weeks after each cycle (nadir day 10-14); UA (hemorrhagic cystitis); BMP; LFTs; fertility preservation discussion; malignancy risk | - | URGENT | ROUTINE | URGENT |
Note: Corticosteroids are generally LESS effective in SPS compared to other autoimmune neurological conditions. IVIg is the preferred first-line immunotherapy (Class I evidence). Rituximab is increasingly used as second-line or IVIg-sparing therapy, though evidence is Class III-IV. Immunotherapy aims to reduce antibody-mediated GABAergic inhibition impairment. Most patients require combination of symptomatic therapy (benzodiazepines) PLUS immunotherapy for optimal outcomes. Treatment is typically lifelong as relapse is common on discontinuation.
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Neurology (neuroimmunology specialist) for diagnosis confirmation, antibody interpretation, immunotherapy guidance, and long-term management plan | STAT | STAT | ROUTINE | STAT |
| Neuromuscular medicine for EMG/NCS to document continuous motor unit activity and confirm electrophysiologic diagnosis | - | URGENT | ROUTINE | - |
| Rheumatology or endocrinology for autoimmune comorbidity management (T1DM, thyroiditis, pernicious anemia, vitiligo) | - | ROUTINE | ROUTINE | - |
| Oncology for paraneoplastic evaluation and tumor management if anti-amphiphysin positive or malignancy identified | - | URGENT | ROUTINE | URGENT |
| Physical therapy for gait training, flexibility, balance assessment, and fall prevention given rigidity and impaired mobility | - | ROUTINE | ROUTINE | ROUTINE |
| Occupational therapy for ADL adaptation, assistive device evaluation, and energy conservation given functional limitations from rigidity | - | ROUTINE | ROUTINE | ROUTINE |
| Pain management for refractory pain and spasms not responding to first-line agents | - | ROUTINE | ROUTINE | - |
| Psychiatry for anxiety and depression management; high prevalence of task-specific phobias and agoraphobia in SPS due to fear of triggering spasms | - | ROUTINE | ROUTINE | - |
| Pulmonology for respiratory function assessment if chest wall rigidity compromises ventilation | - | URGENT | ROUTINE | URGENT |
| Anesthesiology consult for intrathecal baclofen pump trial and surgical planning if refractory to oral medications | - | - | ROUTINE | - |
| Social work for disability resources, home health services, and insurance navigation for IVIg coverage | - | ROUTINE | ROUTINE | - |
| Ophthalmology for visual assessment if anti-GAD associated optic neuropathy or cerebellar involvement | - | ROUTINE | ROUTINE | - |
| Infusion center coordination for IVIg, rituximab, or cyclophosphamide outpatient infusions | - | ROUTINE | ROUTINE | - |
| Neurosurgery consultation for intrathecal baclofen pump implantation if ITB trial successful | - | - | ROUTINE | - |
4B. Patient Instructions¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Return to ED immediately for uncontrolled spasms, difficulty breathing, falls with injury, or inability to walk (may indicate status spasticus requiring ICU care) | Y | Y | Y | - |
| SPS is a chronic, treatable autoimmune condition -- improvement is expected with appropriate therapy but may take weeks to months; this is a lifelong condition requiring ongoing treatment | Y | Y | Y | - |
| Do NOT stop benzodiazepines abruptly as this may trigger life-threatening status spasticus (severe unrelenting spasms, respiratory failure); always taper under physician supervision | Y | Y | Y | - |
| Avoid known triggers for spasms: sudden loud noises, unexpected touch, emotional stress, cold temperatures, sudden movements, and crowded environments | - | Y | Y | - |
| Report signs of infection immediately (fever >100.4F, cough, dysuria, rash) as immunosuppressive therapy (IVIg, rituximab) increases infection risk | - | Y | Y | - |
| Do not drive until cleared by neurology due to risk of sudden spasms, impaired mobility, and medication sedation effects | Y | Y | Y | - |
| Keep a spasm diary tracking frequency, severity, triggers, and medication effects to guide treatment optimization | - | Y | Y | - |
| Monitor blood sugars regularly if diabetic or if starting corticosteroids (steroids significantly elevate blood glucose; SPS has high T1DM comorbidity) | Y | Y | Y | - |
| Avoid live vaccines while on immunosuppressive therapy including rituximab and mycophenolate; inform all physicians and pharmacists of immunosuppression status | - | Y | Y | - |
| Carry medical alert identification (bracelet/card) indicating Stiff Person Syndrome, current medications (especially benzodiazepines and immunotherapy), and emergency contact information | - | Y | Y | - |
| Attend all follow-up appointments -- SPS requires regular monitoring with labs, clinical assessments, and periodic antibody levels | - | Y | Y | - |
| In case of surgery or medical procedure, inform anesthesiologist about SPS (risk of exacerbated spasms with certain anesthetic agents; benzodiazepines must NOT be withheld perioperatively) | - | Y | Y | - |
| Avoid alcohol as it potentiates benzodiazepine sedation and increases fall risk | - | Y | Y | - |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Gentle stretching and range-of-motion exercises daily to maintain flexibility and reduce rigidity; avoid high-impact or startling exercises | - | Y | Y | - |
| Warm-water pool therapy (aquatic physical therapy) as tolerated -- warmth and buoyancy reduce spasm frequency and severity | - | - | Y | - |
| Fall prevention measures at home (remove loose rugs, adequate lighting, grab bars in bathroom, non-slip mats) given rigidity and balance impairment | - | Y | Y | - |
| Stress management techniques (meditation, deep breathing, progressive muscle relaxation, cognitive behavioral therapy) as emotional stress is a common spasm trigger | - | Y | Y | - |
| Adequate sleep (7-8 hours nightly); maintain regular sleep schedule; benzodiazepine dosing may need evening adjustment for nocturnal spasms | - | Y | Y | - |
| Low-impact exercise program as tolerated (walking, stationary cycling, yoga with modifications) to prevent deconditioning from immobility | - | Y | Y | - |
| Temperature regulation: avoid extreme cold which can trigger spasms; dress in layers; maintain comfortable ambient temperature | - | Y | Y | - |
| Assistive device evaluation (cane, walker, wheelchair) based on functional status and fall risk to maintain independence and safety | - | Y | Y | - |
| Vaccinations should be up to date before initiating immunosuppressive therapy (pneumococcal, influenza, hepatitis B, COVID-19); avoid live vaccines on immunosuppression | - | Y | Y | - |
| Bone protection with calcium and vitamin D if on chronic corticosteroids; DEXA scan if steroid use >3 months | - | Y | Y | - |
| Smoking cessation to improve respiratory function and reduce infection risk during immunosuppression | Y | Y | Y | - |
| Support group referral: Stiff Person Syndrome Research Foundation (stiffperson.org) for peer support and disease education | - | - | Y | - |
═══════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| Multiple sclerosis (MS) | Relapsing-remitting course; white matter lesions on MRI; oligoclonal bands; optic neuritis; Lhermitte sign; spasticity from upper motor neuron damage (not rigidity) | MRI brain/spine (periventricular lesions, Dawson fingers); CSF oligoclonal bands; anti-GAD negative; no continuous motor unit activity on EMG |
| Myelopathy (compressive or inflammatory) | Upper motor neuron signs (hyperreflexia, Babinski, spasticity); sensory level; bowel/bladder dysfunction; structural cause on imaging | MRI spine (cord compression or signal change); normal EMG (no CMUA); anti-GAD negative |
| Tetanus | Acute onset; history of wound/infection; trismus (lockjaw); opisthotonus; risus sardonicus; no antibody elevation; self-limited with treatment | Wound culture; tetanus toxin assay; history of incomplete vaccination; anti-GAD negative; EMG may show CMUA but resolves with treatment |
| Neuromyotonia (Isaacs syndrome) | Peripheral nerve hyperexcitability; myokymia; fasciculations; sweating; muscle cramps; anti-CASPR2/anti-LGI1 antibodies; no axial rigidity predominance | EMG (neuromyotonic discharges, myokymic discharges); anti-CASPR2/LGI1 antibodies; anti-GAD negative; distinct EMG pattern from SPS |
| Functional neurological disorder (FND) | Inconsistent symptoms; entrainment; distractibility; positive Hoover sign; no continuous motor unit activity at rest; normal antibodies | EMG normal at rest; anti-GAD negative; positive functional neurological examination findings (Hoover, tremor entrainment); psychiatric comorbidity common |
| Primary lateral sclerosis (PLS) | Progressive spasticity; upper motor neuron signs; no sensory involvement; slow progression over years; no antibody positivity; no episodic spasms | EMG (no CMUA; upper motor neuron pattern); anti-GAD negative; MRI (motor cortex atrophy); slow progression |
| Hereditary spastic paraplegia (HSP) | Family history; progressive lower extremity spasticity; insidious onset; genetic mutations identified | Genetic testing (SPG genes); anti-GAD negative; EMG normal at rest; family history |
| Ankylosing spondylitis | Axial rigidity from joint/ligament pathology; inflammatory back pain; sacroiliac involvement; HLA-B27 positive | X-ray/MRI of sacroiliac joints; HLA-B27; ESR/CRP elevated; anti-GAD negative; EMG normal |
| Parkinson disease | Rigidity (lead-pipe, cogwheel); bradykinesia; resting tremor; asymmetric onset; dopamine-responsive | DAT scan; clinical features (bradykinesia required); anti-GAD negative; EMG shows no CMUA; L-dopa trial |
| Dystonia (generalized or segmental) | Sustained or intermittent muscle contractions causing abnormal postures; task-specific; patterned movements; may have sensory tricks | EMG (patterned co-contraction during movement, not continuous at rest); DYT gene testing; anti-GAD negative; different movement pattern |
| Myotonia (myotonic dystrophy, channelopathies) | Difficulty relaxing muscles; grip myotonia; percussion myotonia; genetic basis; no startle-induced spasms | EMG (myotonic discharges -- dive-bomber sound); genetic testing (DMPK, CNBP, SCN4A, CLCN1); anti-GAD negative |
| Hyperekplexia (startle disease) | Exaggerated startle response from birth/infancy; neonatal stiffness; genetic (GLRA1, GLRB); no progressive rigidity; responds to clonazepam | Genetic testing (glycine receptor mutations); onset in infancy; anti-GAD negative; EMG (startle reflex but no CMUA at rest) |
| Neuroleptic malignant syndrome (NMS) | Acute onset; recent neuroleptic use; hyperthermia; autonomic instability; CK markedly elevated; encephalopathy | Medication history (neuroleptic exposure); CK markedly elevated; hyperthermia; resolves with drug discontinuation |
| Serotonin syndrome | Acute onset; serotonergic drug exposure; clonus (especially lower extremity); hyperreflexia; hyperthermia; agitation | Medication history (serotonergic drugs); clonus (distinct from rigidity); resolves with drug discontinuation and cyproheptadine |
6. MONITORING PARAMETERS¶
6A. Acute Phase Monitoring (Inpatient)¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Spasm frequency and severity assessment (clinical scoring) | Q4h (floor); Q1-2h (ICU) | Decreasing frequency and severity | Increase benzodiazepine dose; consider IV infusion or IVIg/PLEX; assess triggers | STAT | STAT | - | STAT |
| Respiratory status (SpO2, respiratory rate, work of breathing) | Continuous (ICU); Q4h (floor) | SpO2 >94%; RR 12-20; no accessory muscle use | If desaturation or increased work of breathing: ABG; consider ICU transfer; intubation if respiratory failure | STAT | STAT | - | STAT |
| CK (creatine kinase) | Q6-12h if spasms severe | CK <1000 U/L | If CK >5000: aggressive IV hydration; urine alkalinization; monitor for AKI; if >10,000: consider ICU | STAT | STAT | - | STAT |
| Renal function (BUN/Cr) | Q12-24h; Q6h if rhabdomyolysis | Stable creatinine | If rising: increase hydration; hold nephrotoxics; nephrology consult | URGENT | URGENT | - | STAT |
| Urine output | Q1h (ICU); Q4h (floor) | >0.5 mL/kg/hr | If oliguric with elevated CK: aggressive hydration; bicarbonate infusion; nephrology consult | URGENT | URGENT | - | STAT |
| Blood glucose | Q6h if on steroids or T1DM comorbidity | <180 mg/dL | Insulin sliding scale; endocrine consult if persistent >250 | STAT | STAT | - | STAT |
| Sedation level (RASS or equivalent) | Q2-4h if on high-dose benzodiazepines | RASS 0 to -1 (alert to mildly sedated) | If over-sedated: reduce benzodiazepine dose; assess for respiratory compromise; hold dose and reassess | URGENT | URGENT | - | STAT |
| Blood pressure and heart rate | Q1h (ICU); Q4h (floor) | SBP 100-160; HR 60-100 | Autonomic instability: consider ICU; treat HTN crisis; assess for PERM variant | STAT | ROUTINE | - | STAT |
| Temperature | Q4h; continuous in ICU | 36.0-38.0C | If hyperthermia with spasms: aggressive cooling; dantrolene; rule out infection; NMS differential | STAT | ROUTINE | - | STAT |
| Electrolytes (Na, K, Ca, Mg, Phos) | Q12-24h; Q6h if rhabdomyolysis | Normal ranges | Correct abnormalities; hypokalemia and hypocalcemia worsen spasms | URGENT | ROUTINE | - | STAT |
6B. Outpatient/Long-Term Monitoring¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Neurological examination (rigidity, spasm frequency, gait, balance, functional status) | Monthly x 6 months; then q3 months | Stable or improving; functional independence maintained | Treatment escalation; add immunotherapy; adjust symptomatic medications | - | - | ROUTINE | - |
| Functional status assessment (modified Rankin Scale, timed walk, activities of daily living) | Q3 months | Stable or improving | Physical therapy intensification; medication adjustment; consider intrathecal baclofen if deteriorating | - | - | ROUTINE | - |
| Anti-GAD65 antibody titer (serum) | Q6-12 months | Stable or declining titers | Rising titers may precede clinical relapse; consider treatment intensification (note: titer does not always correlate with disease activity) | - | - | ROUTINE | - |
| CBC with differential | Monthly on immunosuppressants (mycophenolate, azathioprine); q2-4 months on rituximab | WBC >3.0; ANC >1.5; Plt >100 | Hold/reduce immunosuppression; growth factor if needed | - | - | ROUTINE | - |
| LFTs (ALT, AST, ALP, bilirubin) | Monthly on azathioprine/mycophenolate; q3 months on other agents | ALT/AST <3x ULN | Dose reduction or switch agent | - | - | ROUTINE | - |
| Renal function (BUN/Cr) | Q3 months; before each IVIg cycle | Stable | Dose adjustment; switch to sucrose-free IVIg product if renal function declining | - | - | ROUTINE | - |
| Quantitative immunoglobulins (IgG, IgA, IgM) | Q6 months on rituximab; annually on other agents | IgG >400 mg/dL | Immunoglobulin replacement if recurrent infections with hypogammaglobulinemia | - | - | ROUTINE | - |
| CD19/CD20 B-cell counts | Q3-6 months on rituximab | B-cell depletion maintained | Re-dose rituximab when B-cells reconstitute (>1% CD19) and clinical worsening | - | - | ROUTINE | - |
| Blood glucose and HbA1c | Q3-6 months (T1DM comorbidity); more frequently if on steroids | HbA1c <7% if diabetic | Endocrine management; insulin adjustment; steroid dose reduction if possible | - | - | ROUTINE | - |
| Thyroid function (TSH) | Annually | Normal | Thyroid hormone replacement if hypothyroid; endocrine referral | - | - | ROUTINE | - |
| DEXA scan (bone density) | Baseline if steroids >3 months; repeat q1-2 years | T-score >-2.5 | Bisphosphonate therapy; calcium/vitamin D; endocrine referral | - | - | ROUTINE | - |
| Paraneoplastic cancer screening | Annually for first 5 years if anti-amphiphysin positive; q2 years if anti-GAD only | No malignancy | Oncology referral if abnormal; intensify screening | - | - | ROUTINE | - |
| LFTs on tizanidine | Baseline, 1, 3, 6 months, then periodically | ALT/AST <3x ULN | Discontinue tizanidine if significant hepatotoxicity | - | - | ROUTINE | - |
| Fall risk reassessment | Q3-6 months | No falls; safe mobility | Adjust PT program; assistive devices; medication review (benzodiazepine dose optimization) | - | - | ROUTINE | - |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Discharge home | Spasms controlled on oral medications; able to ambulate safely (with or without assistive device); ADLs independent or with available home support; no respiratory compromise; CK trending down; follow-up with neurology within 1-2 weeks; medication education completed; triggers identified and avoidance plan discussed; family/caregiver education completed |
| Admit to floor (neurology) | New-onset SPS requiring diagnostic workup (LP, EMG, antibodies, imaging); uncontrolled spasms requiring IV benzodiazepines or medication titration; need for IVIg initiation; elevated CK from spasm-related rhabdomyolysis; functional decline requiring inpatient rehabilitation evaluation; new paraneoplastic workup needed |
| Admit to ICU | Status spasticus (severe unrelenting spasms); respiratory compromise from chest wall rigidity; need for mechanical ventilation; rhabdomyolysis with CK >10,000 or acute kidney injury; autonomic instability; need for continuous benzodiazepine or propofol infusion; PERM variant with encephalopathy and autonomic dysfunction |
| Transfer to higher level of care | Neuroimmunology specialist not available; neuromuscular EMG expertise not available; IVIg/plasmapheresis not available; intrathecal baclofen pump services not available; ICU care required when not available at current facility |
| Inpatient rehabilitation | Significant functional impairment from rigidity and spasms; medically stable; expected to benefit from intensive PT/OT; unable to safely return home; needs supervised medication titration and mobility training |
| Outpatient follow-up | All discharged patients: neurology follow-up within 1-2 weeks; labs per monitoring schedule; ongoing IVIg scheduling if initiated; physical therapy referral; paraneoplastic screening completion if not done inpatient |
| Readmission criteria | Uncontrolled spasms despite medication compliance; respiratory difficulty; falls with injury; status spasticus; suspected rhabdomyolysis (dark urine, severe muscle pain after spasms); infection on immunosuppression |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| IVIg for SPS (Class I RCT -- gold standard evidence for SPS immunotherapy) | Class I, Level A | Dalakas MC et al. N Engl J Med 2001;345:1870-1876 |
| Anti-GAD65 antibodies as primary diagnostic marker for SPS (~80% positive) | Class II, Retrospective | Solimena M et al. N Engl J Med 1990;322:1555-1560 |
| Clinical spectrum and natural history of SPS | Class III, Retrospective | Dalakas MC. Curr Treat Options Neurol 2009;11:102-110 |
| Comprehensive review of SPS spectrum disorders (classic, SLS, PERM) | Expert Review | Dalakas MC. N Engl J Med 2024;390:1935-1948 |
| EMG findings: continuous motor unit activity at rest in SPS | Class II | Gordon EE et al. Am J Med 1967;42:582-599 |
| Original description of stiff-man syndrome (Moersch and Woltman) | Historical | Moersch FP, Woltman HW. Proc Staff Meet Mayo Clin 1956;31:421-427 |
| Anti-amphiphysin antibodies and paraneoplastic SPS | Class III | De Camilli P et al. N Engl J Med 1993;328:546-551 |
| Diazepam as first-line symptomatic treatment for SPS | Expert Consensus | Dalakas MC. Curr Treat Options Neurol 2009;11:102-110 |
| Baclofen as adjunctive therapy for rigidity and spasms in SPS | Class IV, Case Series | Stayer C, Tronnier V. J Neurol 1997;244:244-245 |
| Anti-glycine receptor antibodies in PERM variant | Class III | Carvajal-Gonzalez A et al. JAMA Neurol 2014;71:1009-1016 |
| Anti-DPPX antibodies and hyperexcitability syndrome including SPS spectrum | Class III | Boronat A et al. Neurology 2013;80:1133-1139 |
| Rituximab for SPS (case series showing benefit) | Class IV, Case Series | Dalakas MC et al. Ann Neurol 2017;82:271-277 |
| Plasmapheresis for acute SPS exacerbations | Class IV, Case Reports | Shariatmadar S, Noto TA. J Clin Apher 2001;16:55-59 |
| Intrathecal baclofen for refractory SPS | Class IV, Case Reports | Stayer C et al. J Neurol 1997;244:244-245 |
| Association of SPS with type 1 diabetes mellitus (30-60% comorbidity) | Class II, Retrospective | Baizabal-Carvallo JF, Jankovic J. J Neurol 2015;262:2030-2040 |
| Paraneoplastic SPS: cancer screening recommendations | Expert Consensus | Titulaer MJ et al. J Neurol Neurosurg Psychiatry 2008;79:1304-1306 |
| High-titer anti-GAD (>2000 IU/mL) differentiates SPS from T1DM | Class II | Saiz A et al. Arch Neurol 2008;65:889-894 |
| SPS and autoimmune comorbidities (thyroiditis, pernicious anemia, vitiligo) | Class III | Alexopoulos H, Dalakas MC. Neurol Neuroimmunol Neuroinflamm 2019;6:e571 |
| Status spasticus as a medical emergency in SPS | Class IV, Case Reports | Stiff-person syndrome and status spasticus. Neurology 2008;71:2093-2094 |
| CSF anti-GAD antibodies and intrathecal synthesis in SPS | Class III | Dalakas MC et al. Neurology 2001;57:780-784 |
| Updated diagnostic criteria and classification of SPS spectrum | Expert Review | Newsome SD, Johnson T. J Neuroimmunol 2022;369:577915 |
| Mycophenolate as immunosuppressive agent in SPS | Class IV, Case Series | Expert consensus; limited published evidence; extrapolated from autoimmune neurology practice |
| GABAergic pathway dysfunction as pathophysiology of SPS | Class II, Basic Science | Levy LM et al. N Engl J Med 1999;341:1511-1516 |
CLINICAL DECISION SUPPORT NOTES¶
Diagnostic Criteria for Stiff Person Syndrome (Dalakas Criteria)¶
All of the following must be present: - [ ] Progressive rigidity and stiffness of axial muscles (trunk, abdomen) and proximal limb muscles - [ ] Superimposed episodic spasms triggered by unexpected stimuli (noise, touch, emotional stress) - [ ] Continuous motor unit activity on EMG (in agonist and antagonist muscles simultaneously) - [ ] Absence of other neurological or cognitive signs to explain stiffness (normal brain/spine MRI) - [ ] Positive serology for anti-GAD65 antibodies (present in ~80%) or other SPS-associated antibodies - [ ] Response to benzodiazepines (supports diagnosis; not required)
SPS Spectrum Variants¶
| Variant | Key Features | Antibodies | Prognosis |
|---|---|---|---|
| Classic SPS | Axial and proximal limb rigidity; episodic spasms; symmetric; anti-GAD65 positive | Anti-GAD65 (~80%) | Generally favorable with treatment; chronic course |
| Stiff-Limb Syndrome (SLS) | Asymmetric limb rigidity; often one leg affected; may be focal | Anti-GAD65 (variable) | Moderate; may evolve to classic SPS |
| PERM | Brainstem/spinal cord involvement; myoclonus; encephalopathy; autonomic dysfunction; most severe | Anti-GlyR; Anti-DPPX; Anti-GAD65 | Poorest; may be monophasic or relapsing |
| Paraneoplastic SPS | Associated with cancer (breast, lung, thymoma); may be any phenotype | Anti-amphiphysin (~100%); Anti-GAD65 (variable) | Depends on tumor response; may improve with cancer treatment |
Anti-GAD65 Titer Interpretation¶
| Titer Range | Clinical Significance |
|---|---|
| Negative (<5 IU/mL) | Does not exclude SPS (seronegative variant exists); consider CSF testing |
| Low-moderate (5-2000 IU/mL) | More commonly T1DM, autoimmune thyroiditis, cerebellar ataxia; less specific for SPS |
| High (>2000 IU/mL) | Highly suggestive of SPS spectrum; also seen in anti-GAD cerebellar ataxia and autoimmune epilepsy |
| Very high (>10,000 IU/mL) | Strongly associated with SPS; check for intrathecal synthesis |
EMG Findings in SPS¶
- Continuous motor unit activity (CMUA): Normal-appearing motor units firing continuously in agonist and antagonist muscles simultaneously at rest
- Co-contraction pattern: Simultaneous activation of opposing muscle groups (e.g., paraspinal extensors and rectus abdominis)
- No voluntary suppression: CMUA persists despite attempts to relax
- Abolition with benzodiazepines: CMUA decreases or resolves with IV diazepam (diagnostic challenge)
- Normal nerve conduction studies: NCS typically normal; no neuromyotonic discharges (distinguishes from Isaacs syndrome)
- No denervation potentials: No fibrillations or positive sharp waves (distinguishes from motor neuron disease)
Red Flags Suggesting SPS¶
- Progressive axial rigidity with preserved cognition
- Episodic painful spasms triggered by startle or emotional stress
- Hyperlordosis of lumbar spine with board-like abdominal muscles
- Difficulty turning or bending at the waist
- Falls without obvious cause (rigid legs "like walking on stilts")
- Comorbid T1DM in patient with unexplained rigidity
- Task-specific phobias (fear of walking, crossing streets) due to spasm anticipation
- Normal brain MRI with prominent rigidity
Status Spasticus Emergency Protocol¶
- Immediate: Diazepam 10-20 mg IV push; may repeat q5-10 min
- If refractory: Midazolam 0.05-0.2 mg/kg/hr IV continuous infusion (ICU with intubation ready)
- If still refractory: Propofol infusion 20-50 mcg/kg/min (requires intubation)
- Concurrent: IV fluids for rhabdomyolysis prevention; CK monitoring; IVIg or PLEX if not recently administered
- Avoid: Abrupt benzodiazepine withdrawal; triggers (minimize stimulation, dark quiet room)
- Monitor: Continuous SpO2; CK q6h; renal function; electrolytes; temperature
CHANGE LOG¶
v1.1 (January 30, 2026)
- Standardized all treatment table dosing to structured [dose] :: [route] :: [frequency] :: [full_instructions] format per C1-C4
- Section 3A: Fixed diazepam IV, lorazepam, midazolam, propofol, IV crystalloid, dantrolene dosing cells (M1)
- Section 3B: Fixed diazepam PO, baclofen, gabapentin, pregabalin, tizanidine, clonazepam, levetiracetam, duloxetine, sertraline dosing cells (M2)
- Section 3C: Fixed IVIg, plasmapheresis, botulinum toxin dosing cells (M3)
- Section 3D: Fixed mycophenolate, azathioprine, prednisone dosing cells; rituximab and cyclophosphamide already correct (M4)
- Added REVISED date to metadata
v1.0 (January 30, 2026) - Initial creation - Section 1: 18 core labs (1A), 19 extended labs (1B), 7 rare/specialized tests (1C) - Section 2: 6 essential imaging/studies (2A), 9 extended (2B), 4 rare/specialized (2C), 10 LP/CSF studies - Section 3: 4 subsections: - 3A: 6 acute/emergent treatments (diazepam IV, lorazepam, midazolam infusion, propofol, IV fluids, dantrolene) - 3B: 9 symptomatic treatments (diazepam PO, baclofen, gabapentin, pregabalin, tizanidine, clonazepam, levetiracetam, duloxetine, sertraline) - 3C: 4 second-line treatments (IVIg, plasmapheresis, intrathecal baclofen, botulinum toxin) - 3D: 5 disease-modifying/immunotherapy (rituximab, mycophenolate, azathioprine, prednisone, cyclophosphamide) with Pre-Treatment Requirements - Section 4: 14 referrals (4A), 13 patient instructions (4B), 12 lifestyle/prevention items (4C) - Section 5: 14 differential diagnoses with distinguishing features - Section 6: 10 acute monitoring parameters (6A), 14 outpatient/long-term monitoring parameters (6B) - Section 7: 7 disposition criteria - Section 8: 23 evidence references with PubMed links - Clinical Decision Support Notes: Dalakas diagnostic criteria, SPS spectrum variants table, anti-GAD titer interpretation, EMG findings summary, red flags checklist, status spasticus emergency protocol
APPENDIX A: SPS Treatment Algorithm¶
Step 1 - Symptomatic Therapy (ALL patients): - Diazepam 5 mg TID, titrate to 20-60+ mg/day (first-line) - Add baclofen 5 mg TID, titrate to 40-80 mg/day (adjunctive) - Add gabapentin/pregabalin if additional benefit needed
Step 2 - First-line Immunotherapy (most patients): - IVIg 2 g/kg over 5 days, repeat q4-6 weeks (Class I evidence) - Assess response at 3 months
Step 3 - Second-line Immunotherapy (IVIg failure or partial response): - Add rituximab 1000 mg x 2 (day 0, day 14), repeat q6 months - OR add mycophenolate/azathioprine as IVIg-sparing
Step 4 - Refractory Disease: - Plasmapheresis for acute flares - Intrathecal baclofen pump for medication-refractory rigidity - Cyclophosphamide as last resort
Step 5 - Paraneoplastic SPS: - Aggressive cancer screening and treatment - Immunotherapy as above - Tumor treatment may improve neurological symptoms
APPENDIX B: Anesthetic Considerations in SPS¶
Perioperative management is critical in SPS patients:
| Consideration | Recommendation |
|---|---|
| Benzodiazepines | Do NOT withhold perioperatively; abrupt withdrawal triggers status spasticus |
| Anesthetic agents | Regional anesthesia preferred when feasible; general anesthesia safe with appropriate monitoring |
| Neuromuscular blockers | Depolarizing agents (succinylcholine) may trigger severe spasms -- AVOID; non-depolarizing agents safe |
| Propofol | Safe and effective; GABAergic mechanism beneficial |
| Opioids | Use cautiously; may exacerbate rigidity in some patients |
| Temperature | Monitor closely; spasm-related hyperthermia possible |
| Positioning | Careful positioning due to fixed rigidity; avoid forced range of motion |
| Postoperative | Resume oral benzodiazepines as soon as possible; IV benzodiazepines if NPO; high risk for spasm exacerbation with pain/stress |