A dual manifestation of GAD-antibody spectrum disorder: a case of progressive encephalomyelitis with rigidity, myoclonus and autoimmune epilepsy with mesial temporal sclerosis

Abstract

Background

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological disorder within the spectrum of stiff-person syndrome (SPS) and epilepsy, and is part of the group of GAD (glutamic acid decarboxylase) antibody-associated disorders. PERM diagnosis is often challenging due to its heterogeneous presentation, and treatment remains difficult, as clear therapeutic guidelines for this condition have yet to be established. To the best of our knowledge, no prior reports have documented the simultaneous occurrence of PERM and anti-GAD–positive autoimmune epilepsy associated with mesial temporal sclerosis (MTS), thus highlighting a previously unrecognised phenotype within the GAD-spectrum disorders.

Case report

We present the case of a 32-year-old male with a progressive neurological syndrome characterised by lower limb rigidity, gait disturbance, painful spasms, and hyperekplexia. Over five years, he developed epileptic seizures, stimulus-induced myoclonus, and neuropsychiatric symptoms (emotional lability, depressive affect, anxiety). High titers of anti-GAD antibodies in serum, along with EMG findings, supported the diagnosis of PERM. Brain MRI revealed right MTS. Symptomatic treatment with GABAergic agents led to significant clinical improvement; immunotherapy was considered but not initially required due to the positive response.

Conclusions

This case represents, to the best of our knowledge, the first reported instance of PERM coexisting with anti-GAD–positive autoimmune epilepsy and MTS, underscoring the clinical relevance of recognizing overlapping GAD-spectrum phenotypes to guide timely diagnosis and individualized management.

Introduction

PERM is a rare and severe immune-mediated disorder of the central nervous system [1, 2] considered both a variant within the spectrum of SPS, and a GAD antibody-associated disorders [3], a range of clinical conditions with heterogeneous manifestations and overlapping symptomatology, all of which are associated with elevated titres of anti-GAD antibodies.

GAD is a rate-limiting enzyme in the conversion of glutamate to GABA. It exists in two isoforms: GAD65 and GAD67, the latter of which has no known clinical significance, and has a molecular structure characterised by an N-terminal domain, a catalytic domain, and a C-terminal domain. Antibodies against GAD specifically recognise and bind to GAD65 epitopes and are found in both the serum and cerebrospinal fluid of patients with GAD antibody–associated disorders. Although the direct pathogenic role of these antibodies remains a matter of debate due to conflicting evidence, sufficient data support their association with impaired GABAergic synaptic transmission [4].

The clinical spectrum of GAD antibody-associated disorders encompasses the SPS and its variants (such as the PERM variant), autoimmune epilepsy, cerebellar ataxia, and limbic encephalitis [5], sharing two main mechanisms from a pathogenic perspective: first, a disruption of reciprocal GABAergic inhibition and a state of hyperexcitability, as a consequence of low GABA levels and impaired GABAergic synaptic transmission. The second is evidenced by antibodies against GAD and other neuronal receptors, intrathecal immunoglobulin synthesis (as demonstrated by the presence of oligoclonal bands in the cerebrospinal fluid), and the involvement of T cell–mediated cellular immunity [5].

The clinical features of PERM include muscle rigidity (both axial and limb), stimulus-induced myoclonus, epileptic seizures and painful spasms [2, 3, 6]. PERM may also be associated with hyperekplexia, reflecting brainstem dysfunction [3, 7], altered consciousness, cerebellar ataxia, respiratory failure, dysphagia and autonomic dysfunction [8, 9]. PERM is also associated with other autoimmune conditions such as thyroid disorders and diabetes [9], and other auto-antibodies positivity, like dipeptidyl-peptidase-like protein-6 (DPPX), amphiphysin, and the glycine receptor (GlyR) antibodies [10, 11], the latter, is associated with a disruption in inhibitory glycine synaptic transmission, specially in the spinal cord and brainstem [8].

In addition, cerebrospinal fluid (CSF) analysis may reveal pleocytosis and oligoclonal bands, indicating intrathecal synthesis of immunoglobulins and serving as a marker of inflammation. Electrophysiological studies have revealed continuous motor-unit firing at rest, confirming that co-contractions of agonist and antagonist muscles cause stiffness [6, 10, 12]. Immunomodulatory treatments, such as corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis, or cyclophosphamide, have been reported to be effective therapies [3, 13].

In this context, we describe a patient who uniquely embodies this complexity, presenting with simultaneous features of PERM and autoimmune epilepsy with MTS, thereby expanding the clinical spectrum of GAD autoimmunity. Due to its atypical clinical presentation mimicking other neurological disorders, the diagnostic difficulty, and the limited information describing the full spectrum of manifestations, particularly the PERM co-occurrence with epileptic phenotypes associated with MTS in the context of GAD autoimmunity, this report aims to contribute to a better understanding of the clinical spectrum of PERM and GAD-associated neurological disorders. To our knowledge, this represents the first reported case of concurrent PERM and autoimmune epilepsy with MTS associated with GAD antibodies. This case underscores the importance of early recognition of overlapping autoimmune neurological syndromes, as timely immunotherapy may significantly improve outcomes.

Case report

A 32-year-old Hispanic male patient with a past medical history of hypothyroidism treated with levothyroxine and no significant family history, presented to the neurology service in 2024 with a five-year history of progressive lumbar pain associated with rigidity in the left lower limb, which began in 2019. He sought neurosurgical evaluation multiple times; however, only symptomatic pain management was advised.

This rigidity impaired gait initiation and maintenance, and by 2020 progressed to involve the contralateral lower limb. The patient experienced painful spasms in the lumbar paravertebral and abdominal wall muscles, triggered by auditory, tactile, and thermal stimuli, particularly cold exposure and emotional stress, as well as hyperekplexia.

As the disease evolved, painful spasms were primarily observed in the lumbar paravertebral and abdominal wall muscles, triggered by sudden auditory or tactile stimuli, as well as abrupt temperature changes—particularly cold exposure—and emotional stress. Subsequently, the patient developed stimulus-sensitive myoclonus, characterized by brief, shock-like jerks predominantly affecting the lower limbs, sometimes spreading to the trunk and upper limbs. Clinically, these myoclonic jerks were differentiated from spasms by their shorter duration, synchronous onset, and absence of sustained contraction or rigidity.

Neuropsychiatric symptoms, including emotional lability, depressed affect, and anxiety, had been present since 2018, coinciding with the onset of seizures. Subsequently, he developed frequent falls, and symptoms of autonomic dysfunction (e.g., diaphoresis and erectile dysfunction) and brainstem involvement (e.g., dysphagia) were also present. A chronological summary of symptom evolution is illustrated (Fig. 1), depicting the temporal progression of neurological and systemic manifestations.

Fig. 1.

Timeline of the 5-year clinical course and key events in the patient with PERM and anti-GAD antibody–associated epilepsy

Epileptic seizures began in 2018, initially characterized by an aura of déjà vu and piloerection, followed by altered consciousness, tonic posturing, and clonic movements of all four limbs lasting approximately two minutes, once leading to bilateral shoulder fracture and dislocation. He had previously been treated with various antiseizure medications, including phenytoin, carbamazepine, and valproic acid, which were discontinued due to adverse effects and lack of seizure control. He is currently managed with levetiracetam 1000 mg tid, with adequate seizure control.

This timeline summarizes the chronological progression of symptoms and major diagnostic milestones over a five-year period. The patient initially presented in 2018 with neuropsychiatric symptoms (emotional lability, anxiety, and depressed mood) and focal seizures characterized by a déjà vu aura with secondary generalization. In 2019, he developed lumbar pain and unilateral lower-limb rigidity, which progressed in 2020 to bilateral rigidity, painful spasms, and hyperekplexia triggered by tactile, auditory, and thermal stimuli. Between 2021 and 2023, autonomic and brainstem features emerged, including diaphoresis, erectile dysfunction, dysphagia, and frequent falls. In 2024, the patient was diagnosed with PERM associated with high-titer anti-GAD antibodies, showing marked symptomatic improvement following GABAergic therapy.

Neurological examination revealed increased muscle tone and hyperreflexia in all four limbs, paravertebral muscle hypertrophy with decreased range of motion, and lumbar hyperlordosis (Fig. 2). Gait evaluation revealed a wide-based and en bloc movement of the limbs. The patient also presented stimulus-induced myoclonus triggered by auditory and tactile inputs.

Fig. 2.

Lumbar hyperlordosis is observed, caused by hypertrophy of the paravertebral muscles

Psychiatric evaluation revealed affective and anxiety symptoms, including depressed mood, persistent worry, and emotional lability. Passive suicidal ideation was noted, without active intent or planning. Cognitive assessment revealed impairment in recent memory, particularly affecting short-term encoding and retention, as well as significantly reduced sustained attention, indicating dysfunction in both executive and memory domains.

The diagnostic workup included screening for paraneoplastic syndromes, thyroid function, nutritional deficiencies, autoimmunity, and CSF analysis, all of which were within normal limits. Brain MRI revealed MTS, predominantly affecting the right hippocampus (Fig. 3). Anti-GAD antibodies in serum were positive at a high titer (93.04 U/mL; reference range < 1.0 U/mL). EEG monitoring during wakefulness was normal. EMG of the affected muscles showed increased insertional activity and large polyphasic motor units at rest and during voluntary activity, predominantly in the proximal muscles. A summary of diagnostic findings is shown in Table 1.

Fig. 3.

Brain MRI, coronal view: A T2-weighted sequence; B TIRM dark fluid sequence that shows asymmetry between both hippocampi, with the right hippocampus appearing smaller and atrophic, consistent with right MTS

Table 1.

Summary of diagnostic workup

Category	Test/Modality	Findings
Imaging	Contrast-enhanced brain MRI	MTS, predominantly right hippocampal involvement. No hyperintense lesions were identified in the brainstem or spinal cord on MRI.
	Cervical spine MRI	Mild right convex cervical scoliosis
	Thoracic spine MRI	Proximal thoracic scoliosis with left convexity and right thoracolumbar curvature
	Lumbosacral spine MRI	Disc disease at L3-L4 and L5-S1
	Abdominal and pelvic CT	Within normal limits
Laboratory Tests	Vitamin B1, B6, B12, Folic acid, Magnesium, Calcium, Phosphorus	All within normal limits
	Creatinine, BUN, Urea, Potassium, Sodium	Normal
	HbA1c	Normal
	CPK	293 U/L (Reference range 10.0–190.0 U/L)
	AST, ALT (GOT, GPT)	Normal
	HTLV-II antibodies	Normal
	TSH and Free T4	Normal
	Methylmalonic acid (serum)	< 0.08 µmol/L (Normal)
	Anti-neuronal antibodies (Anti-Hu, Yo, Ri, Amphiphysin, CV2), serum	Not detected
	Anti-GAD antibodies serum	Positive – 93.04 U/mL (Reference range < 1.0 U/mL)
	HIV, CRP	Negative/Normal
CSF Analysis	Cell count value Protein value Glucose value Lactic acid, Albumin, Total Protein, Glucose	0.010 cells/µL, (PMNs 10%, MN 90%) 25.6 mg/dL 92 mg/dL. Within normal limits
	Gram stain, Culture, KOH prep, India ink	Negative
	AFB smear, HSV I/II, CMV, EBV, Toxoplasma	All negative
	Non-treponemal test	Negative
	ME FilmArray panel	No pathogens detected
	Mycobacterium DNA and drug resistance	Not detected
	Anti-neuronal antibodies anti-Hu, anti-Yo, anti-Ri, anti-Amphiphysin, and anti-CV2, anti-Ma2, MGT-30, AGNA, Recoverine antibodies, CSF	Not detected
Electrophysiology	Electromyography (EMG)	Increased insertional activity was observed in all examined muscles, with abundant large polyphasic motor units present both at rest and during voluntary activity, predominantly in the proximal musculature. (Biceps, rectus abdominis, vastus lateralis, lumbar paraspinals, tibialis anterior)
	Electroencephalogram (EEG)	EEG monitoring during wakefulness was normal, with a total duration of one hour, using a bipolar longitudinal montage. Hyperventilation and photic stimulation were performed as activation procedures, without abnormal findings

A diagnosis of a SPS variant— PERM was made. Pharmacological treatment was initiated with a GABAergic agonist, clonazepam 1 mg orally every 8 h, resulting in significant clinical improvement within 24 h of starting treatment, characterized by a noticeable reduction in muscle rigidity, decreased frequency and intensity of painful spasms, and improved gait stability. The patient continues to be followed up regularly in our neurology clinic. After initiating clonazepam, he experienced moderate clinical improvement, with partial reduction of rigidity and painful spasms during follow-up.

Discussion

PERM was first described by Whiteley et al. [9] as a rare variant of the SPS spectrum. PERM pathophysiology is primarily mediated by autoimmune mechanisms that disrupt inhibitory neurotransmission, particularly affecting GABAergic and glycinergic pathways [3, 10, 11]. Autoantibodies targeting glutamic acid decarboxylase (GAD), the rate-limiting enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), were initially identified in patients with stiff person syndrome (SPS), epilepsy, and type 1 diabetes mellitus (T1DM). More recently, they have been implicated in a broader range of neurological autoimmune disorders associated with increased neuronal excitability, collectively referred to as GAD antibody-spectrum disorders (GAD-SD). In these conditions, disrupted GABAergic neurotransmission—presumably mediated by GAD autoantibodies—leads to neuronal hyperexcitability, affecting both spinal circuits (manifesting as rigidity) and hippocampal networks (resulting in seizures and hippocampal sclerosis) [5]. This dual mechanism provides a plausible explanation for the coexistence of PERM and epilepsy observed in our patient. Also, studies have found that PERM is closely associated with other autoimmune diseases such as thyroid disorders and diabetes [14]. A systematic PubMed search using the MeSH terms “Progressive Encephalomyelitis with Rigidity and Myoclonus”, “Autoimmune Epilepsy with Mesial Temporal Sclerosis”, “Anti-GAD Antibodies” and “GAD Spectrum Disorders” returned no previous reports describing a patient with the simultaneous occurrence of PERM and anti-GAD–positive autoimmune epilepsy with MTS, suggesting that the present case is, to the best of our knowledge, unique.

Currently, no standardised diagnostic guidelines exist for PERM, but in 2022, Newsome and Johnson proposed diagnostic criteria for stiff-person spectrum disorders (SPS-SD), which include PERM as a variant [15].

Our patient presented with typical clinical features of PERM, fulfilling the definitive diagnostic criteria due to the presence of axial and appendicular rigidity, painful spasms, and stimulus-induced myoclonus [1, 2], with the presence of high titers of serum autoantibodies of glutamic acid decarboxylase and an EMG demonstrating continuous motor unit activity in the affected muscles. Notably, the presence of epileptic seizures and mood disturbances reflects the diffuse involvement of the central nervous system that characterises this syndrome [3, 6]. Clinically observed lumbar hyperlordosis and paravertebral muscle hypertrophy, likely due to sustained muscle contraction, further supported our diagnostic suspicion [2].

A key finding in this case was the presence of high titers of anti-GAD65 antibodies. While not exclusive to PERM, their presence—together with the clinical and electrophysiological findings—strongly supported the diagnosis [10, 11]. The EMG demonstrated increased insertional activity and large polyphasic motor unit potentials in proximal muscles, consistent with previous reports in PERM patients [1, 6, 8]. Moreover, brain MRI revealed right MTS. Hippocampal involvement, including sclerosis, has been described in patients with anti-GAD65 antibodies and epilepsy [16, 17], and classified as ILAE type 3 hippocampal sclerosis [18]. This finding in our patient suggests that the epileptic seizures and associated MTS represent another manifestation within the GAD65 antibody–associated neurological spectrum, coexisting with PERM rather than constituting an unrelated comorbidity. Although a secondary consequence of recurrent seizures cannot be completely excluded, the relatively low ictal frequency and disease chronology make this mechanism less likely. Instead, we consider that MTS in this case is more plausibly linked to the underlying autoimmune process mediated by anti-GAD65 antibodies, in line with prior evidence of direct antibody-induced hippocampal injury [16, 17]. Overall, this case underscores the concept of GAD-spectrum disorders as a continuum encompassing diverse but overlapping neurological phenotypes affecting both spinal and limbic inhibitory circuits.

The differential diagnosis considered other antibody-mediated syndromes within the spectrum of stiff-person and autoimmune encephalitis, including anti-glycine receptor (GlyR), dipeptidyl-peptidase-like protein-6 (DPPX), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and amphiphysin antibodies. Anti-GlyR antibodies were not assessed due to insurance coverage limitations; therefore, their contribution cannot be completely excluded. Antibodies against amphiphysin were tested and resulted negative, reducing the likelihood of a paraneoplastic form. In addition, the patient showed no gastrointestinal hyperexcitability symptoms or encephalopathic features typical of DPPX, no faciobrachial dystonic seizures or hyponatremia suggestive of LGI1, and no evidence of peripheral nerve hyperexcitability characteristic of CASPR2 autoimmunity. Taken together, the clinical presentation and serological findings — notably the presence of high anti-GAD antibody titers — strongly supported the diagnosis of a GAD antibody–associated disorder within the stiff-person spectrum.

Although the diagnosis of PERM is clinical, it is often delayed due to its overlap with other neurological conditions such as neuromyelitis optica, autoimmune encephalitis, multiple sclerosis, or functional movement disorders [1, 3, 10]. Its low prevalence and the absence of standardised diagnostic criteria hinder timely recognition [10].

Regarding treatment, our patient showed a favourable response to clonazepam, a first-line GABAergic agent used in both SPS and PERM [3]. However, optimal management often requires aggressive immunotherapy with corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis, or immunosuppressants such as cyclophosphamide or rituximab [3, 13]. Although immunotherapy was not initially necessary in our patient due to a good clinical response to GABAergic treatment, we acknowledge that disease progression and relapses are common and may warrant immunotherapy in later stages. Indeed, Fogan et al. reported responsiveness to plasmapheresis and immunosuppression in progressive encephalomyelitis with rigidity [13]. More recently, Mercure-Corriveau et al. described significant improvement in Stiff Person Spectrum Disorders, including PERM, using a multimodal approach involving plasmapheresis and immunosuppressants [19].

The clinical relevance of this case is underscored by the prolonged five-year diagnostic delay and its multisystemic neuropsychiatric manifestations, which reflect the disease’s multisystemic nature. Despite its rarity, clinical neurologists need to recognise the characteristic clinical pattern of PERM, as early diagnosis and treatment can significantly improve quality of life and reduce morbidity and mortality [3, 6, 20].

In conclusion, this case report describes a patient with PERM and coexisting epilepsy with MTS, unified by the presence of high-titer anti-GAD antibodies. It highlights the protracted diagnostic journey often faced by these patients and underscores the importance of considering GAD-SD in patients presenting with complex neurological syndromes involving stiffness, myoclonus, and epilepsy. Moreover, several studies describe patients who, over time, develop additional disorders within the same spectrum. This observation raises the question of whether these conditions represent not merely a cluster of distinct diseases, but rather a continuum within the GAD antibody-related neurological syndromes [21–24].

By detailing this specific constellation of findings, we aim to broaden the recognised clinical spectrum of GAD autoimmunity and reinforce the need for a high index of suspicion to facilitate early diagnosis and appropriate management.

Authors’ contributions

Conceptualization: M.L.-L., M.A.-C., C.S.-C., S.G.-U., V.B., D.R.-P. and J.V.-M.Investigation: M.L.-L., M.A.-C., C.S.-C., S.G.-U. and J.V.-M.Data curation: M.L.-L., M.A.-C., C.S.-C. and S.G.-U.Writing – original draft: M.L.-L., M.A.-C., C.S.-C. and S.G.-U.Writing – review & editing: D.R.-P., J.V.-M. and V.B.Visualisation: D.R.-P. and V.B.Supervision: V.B.All authors read and approved the final manuscript.

Funding

This research was funded by Universidad Simón Bolívar, Vicerrectoría de Investigación, Extensión e Innovación, through internal funds for research strengthening, Barranquilla, Colombia.

Data availability

The datasets used and/or analysed during the current study are not publicly available due to privacy and ethical considerations, but are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee in Investigation of the Caribbean Foundation for the Biomedical Investigation (BIOS) (CEI BIOS – OOOOO1, July 04, 2025). Written informed consent was obtained from the patient for participation in the study and the use of clinical data for research purposes.

Consent for publication

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

Competing interests

The authors declare no competing interests.