Neuroimmunology
Anti-IgLON5 disease
Oct. 10, 2024
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Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies
- Updated 06.07.2023
- Released 05.08.2020
- Expires For CME 06.07.2026
Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies
Introduction
Overview
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a potentially treatable but often life-threatening neurologic disorder. PERM is characterized by progressive muscular rigidity and spasms, myoclonus and hyperekplexia with prominent brainstem signs, long-tract signs, and autonomic dysfunction. In approximately half of patients with PERM, 1-glycine receptor autoantibodies can be detected in serum and/or CSF. The discovery of glycine receptor autoantibodies has revolutionized the treatment of patients with PERM because it is now clear that, despite the severity of the disorder, at least some patients respond to immunomodulatory therapies.
Key points
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• Approximately half of patients with PERM and a minority of patients with stiff-person spectrum disorders have detectable glycine receptor autoantibodies in the serum and/or CSF; some patients have coexisting glutamic acid decarboxylase 65 (GAD65) antibodies. | |
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• Most remaining patients with PERM are “seronegative” or have GAD65 antibodies alone. | |
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• PERM can be paraneoplastic but most cases occur in individuals without an underlying malignancy; approximately one third have other autoimmune disorders. | |
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• Most patients improve with immunomodulatory therapies, though complete neurologic recovery may not occur. | |
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• A significant minority of patients relapses following initial treatment. | |
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• Glycine receptor antibodies have also been reported in other neurologic disorders where their clinical significance is less clear. |
Historical note and terminology
Following the first descriptions of stiff-person syndrome (59), PERM was recognized as a distinct clinical presentation within the stiff-person disorder spectrum, characterized by the unequivocal involvement of the brainstem (83). The possibility of distinct underlying pathogenic mechanisms in PERM compared with classical stiff-person syndrome was put forward in 1999 (10). However, the relatively rapid and relentless progression of PERM led to the widespread belief that the disorder had a paraneoplastic or neurodegenerative basis (04), although notably malignancies were only detected in a minority of cases. The discovery of autoantibodies to glycine receptors in some patients with PERM has led to a shift in understanding of the pathophysiological mechanisms of disease (43; 12). It is now clear that many patients with PERM have an autoimmune disorder and immunomodulatory treatment results in neurologic improvement in many cases.
Glycine receptor autoantibodies were first detected in a patient with PERM in 2008 (43). This patient presented with acquired spontaneous and stimulus-sensitive myoclonus, then went on to develop a more florid clinical syndrome with gaze palsies and severe truncal and lower limb rigidity. It was the similarity of his initial presentation to patients with hereditary hyperekplexia (most commonly caused by mutations in the alpha-1 subunit of the glycine receptor) and the discovery of autoantibodies to neuronal surface antigens occurring in association with acquired CNS disorders (21; 22) that prompted the search for glycine receptor autoantibodies. The index case made a substantial recovery following treatment with corticosteroids, plasmapheresis, intravenous immunoglobulins, and cyclophosphamide. The first series of patients with glycine receptor autoantibodies identified 33 out of 45 patients with high-titer glycine receptor autoantibodies having a clinical diagnosis of PERM and retrospective analysis of a separate cohort of 52 patients with stiff-person spectrum disorders identified a further 11 cases with glycine receptor autoantibodies, five of whom had PERM (12). Glycine receptor autoantibodies were also identified in some patients with other acquired neurologic syndromes including other stiff-person spectrum disorders, brainstem encephalitis, encephalitis with seizures, and optic neuritis. The range of neurologic presentations reported in patients found to harbor glycine receptor antibodies has continued to broaden, though the strongest clinical association is with PERM. Laboratory studies have demonstrated the direct pathogenicity of glycine receptor autoantibodies purified from patients with PERM and stiff-person spectrum disorders (20).
Clinical manifestations
Presentation and course
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• Diagnosis of PERM is clinical and characterized by a combination of muscle rigidity, muscle spasms, myoclonus, dysautonomia, and brainstem dysfunction. |
PERM is a clinical diagnosis characterized by muscle rigidity, muscle spasms, myoclonus, dysautonomia, long tract signs, and evidence of brainstem dysfunction. It is the prominent brainstem features and rapid clinical progression over weeks that distinguish PERM from other stiff-person spectrum disorders. The rigidity and spasms in PERM frequently, and sometimes exclusively, involve the distal limbs, though can also involve the truck and proximal lower limb muscles as in classical stiff-person syndrome (10). Patients are often described as having “plastic rigidity” – increased tone throughout the whole range of passive limb movement (58). Affected muscles may feel “woody” to palpation. Evidence of brainstem involvement may include ophthalmoparesis, nystagmus, opsoclonus, deafness, dysarthria, and dysphagia and may develop before or concurrently with the rigidity and spasms. Many patients develop marked autonomic instability/failure. Patients with PERM may have sensory symptoms and signs including neuropathic pain or itch. Less commonly patients with PERM have seizures or cognitive disturbance indicative of supratentorial involvement.
Approximately half of patients with a clinical diagnosis of PERM do not have antibodies to known neuronal antigens in their serum (51). The most commonly found specific antibody is to the alpha 1 subunit of the glycine receptor, with a small proportion of patients having antibodies to GAD65 (or both glycine receptor antibodies and GAD65 antibodies). There are single case reports for patients with PERM and antibodies associated with paraneoplastic neurologic disorders, anti-amphiphysin, and anti-Ri (46; 53). A very rare variant of PERM has been recognized associated with autoantibodies to DPPX (dipeptidyl-peptidase-like protein 6, a regulatory subunit of Kv4.2 potassium channels). These patients often have myoclonus, hyperekplexia, and rigidity but their neurologic symptoms are preceded by gastrointestinal symptoms, which can be severe and cognitive manifestations are more frequent and severe than in PERM with glycine receptor autoantibodies (08; 37).
The clinical characteristics reported in patients who have positive serum and/or CSF glycine receptor autoantibodies are listed in Table 1. There is a spectrum of disease and individual patients can have different combinations of the features listed (12). There is an approximately even split by gender and the reported cases cover all ages (1 to 75 years) (06). It is interesting that some of the reported cases of PERM with glycine receptor autoantibodies have prominent pain or itch, and a case series highlighted novel visual symptoms (visual snow, spider web-like images forming shapes and 3-D images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia) occurring in some patients with glycine receptor autoantibodies (65). However, further studies are needed to understand if these clinical features can help to distinguish between glycine receptor antibody positive and seronegative cases and it is also possible that other neuronal surface antibodies are present and relate to some of the clinical features (76).
Table 1. Clinical Features in PERM with Glycine Receptor Antibodies
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• Spasms/stiffness/rigidity/myoclonus (neck/trunk/limb muscles) | |
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• Oculomotor disturbance: nerve or supranuclear gaze palsy, eyelid ptosis, diplopia, nystagmus, or slow/jerky saccades | |
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• Trigeminal, facial and bulbar disturbance (dysphagia, dysarthria, difficulty chewing, facial numbness, trismus) | |
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• Hyperekplexia (spontaneous or triggered by noise or touch) | |
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• Walking difficulties/falls, mostly related to stiffness/rigidity/spasms | |
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• Limb paresis/pyramidal signs | |
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• Limb or gait cerebellar ataxia | |
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• Autonomic disturbance (urinary retention is particularly common but hyper/hypohidrosis, dry mouth, brady/tachycardia, hypo/hypertension, bladder, bowel, or sexual dysfunction have all been reported) | |
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• Cognitive impairment/encephalopathy/seizures | |
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• Sensory symptoms/pain/itch | |
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• Respiratory failure (admission in ICU/ventilation) |
Glycine receptor autoantibodies have also been detected in a minority (10% to 15%) of patients with other stiff-person spectrum disorders (56; 51). Some patients with glycine receptor antibodies have a classical presentation of stiff-person syndrome with abdominal and thoraco-lumbar rigidity leading to exaggerated lumbar lordosis, gait disturbance, and falls. They also experience superimposed painful muscle spasms triggered by a variety of stimuli. Other patients have a more anatomically limited variant of stiff-person syndrome predominantly affecting one or more distal limb, termed stiff-limb syndrome. Psychiatric symptoms including task-specific phobias and generalized anxiety disorders are common in these disorders and perhaps more frequent than in PERM. Sweating and tachycardia in association with spasms is common. In contrast to PERM, severe autonomic dysfunction is unusual, brainstem signs are not observed, and clinical progression is slower (months to years). Some of these patients have coexisting GAD65 antibodies (51).
Glycine receptor autoantibodies have also been detected in patients with encephalopathy and/or seizures without features of stiff-person syndrome, brainstem predominant encephalitis, optic neuritis/atrophy, and neuromyelitis optica (85; 12) (Table 2). However, glycine receptor antibodies are detectable at frequencies of up to 6% in some neurologic “control” populations (such as multiple sclerosis), bringing into question their clinical relevance in disorders where they are present in a small minority of cases, and the response to immunotherapy is variable (52). Glycine receptor autoantibodies have also been detected in rare healthy controls or patients with psychosis, though usually at low titers (75). Moreover, in patients with neurologic disorders other than PERM, glycine receptor autoantibodies are usually detected only in the serum whereas in patients with PERM they are almost always also present in the CSF.
A minority (less than 20%) of patients who develop neurologic disorders with glycine receptor autoantibodies have an underlying malignancy, with thymomas and lymphomas most common (Table 3). A substantial proportion of patients have a personal history of other autoimmune disease (Table 4).
Table 2. Neurologic Disorders in Which Serum Glycine Receptor Antibodies Have Been Reported
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• PERM | |
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• Optic neuritis/atrophy | |
Table 3. Neoplasias Associated with Glycine Receptor Autoantibodies and Neurologic Disease
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• Breast cancer | |
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Table 4. Autoimmune Disorders Associated with PERM
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• Psoriasis |
Prognosis and complications
Historical cases of untreated PERM in which the antibody status was not known usually progressed to death within 2 to 3 years. Severe disability due to muscle rigidity is widely reported in untreated PERM and sometimes fractures occur as a result of intense muscle spasms. Deaths can result indirectly from complications of immobility, such as pneumonia or falls (12), or suddenly as a result of autonomic dysfunction or precipitous respiratory failure (24; 25).
Clinical vignette
To illustrate the presentation we present a fictitious case:
A 63-year-old woman with a background of hypothyroidism presented with two weeks of intermittent tingling in the left flank and lower limb and one week of increasing stiffness affecting the feet and ankles, brief jerks triggered by touch and sound, diplopia, and constipation. During this time she fell at home and sustained a fracture to the right wrist. She then developed difficulty swallowing, which precipitated her hospital admission. On initial examination she had muscle rigidity particularly affecting the distal lower limbs. She was globally hyperreflexic with extensor plantar responses. The sensory examination was normal. She had restricted horizontal and vertical eye movements and was dysarthric. Her condition progressed over the next 24 hours and she required intubation for respiratory compromise. Her muscle rigidity became more widespread involving the trunk, all limbs, and the facial muscles and she had an almost complete ophthalmoplegia without doll’s eye movements. She had episodes of diaphoresis accompanied by tachycardia and hypertension.
Her routine blood tests were within normal limits except for a mildly elevated creatine kinase. CSF showed a mild pleocytosis (10 lymphocytes/mm3, normal protein, normal glucose, no oligoclonal bands, negative viral PCR, negative culture). MRI brain and spinal cord were unremarkable. A CT body did not show any evidence of malignancy. EMG showed widespread continuous motor activity in affected muscles. Glycine receptor autoantibodies in the CSF and serum were positive.
She received treatment initially with oral diazepam and high dose intravenous methylprednisolone (started after the imaging but prior to receipt of the serological results). Because there was no clinical improvement, she went on to have plasmapheresis. Following this she made slow clinical improvements and was extubated successfully after a further three weeks on intensive care. Her muscle rigidity, myoclonus, and diplopia all improved further over the course of the next two months and she was discharged from hospital with ongoing rehabilitative treatment. Her prednisolone was weaned off over six months. Unfortunately, 11 months after her original illness the myoclonus and rigidity recurred, prompting retreatment with plasmapheresis as well as cyclophosphamide and rituximab. Her neurologic condition has not recurred following the second treatment.
Cases illustrated with informative videos are available for the index patient and a child with glycine receptor autoantibodies (43; 23).
Biological basis
Etiology and pathogenesis
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• PERM is an autoimmune disorder caused in a substantial number of cases by glycine receptor antibodies. | |
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• The autoantibodies to glycine receptors found in patients are predominantly IgG1 subclass. | |
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• IgG purified from patients with PERM and glycine receptor autoantibodies causes a reduction of glycinergic neurotransmission in cultured motorneurons. |
With the discovery of glycine receptor autoantibodies, PERM is now considered to have an autoimmune pathology in many, if not all, cases. In a small proportion (less than 20%) the disease appears to have a paraneoplastic etiology with thymomas or lymphomas found in some cases. However, the relationship between these tumors and the specific glycine receptor antibodies is unknown. In the majority of patients an underlying malignancy is not found even after years of follow-up. Some patients describe a preceding infectious illness suggesting that mechanisms such as molecular mimicry or a temporary breech in the blood-brain barrier may play a role. A substantial proportion of patients with glycine receptor autoantibodies have other autoimmune diseases such as autoimmune thyroid disease or type 1 diabetes, suggesting that the disease arises more frequently in patients with a propensity to autoimmunity.
The first pieces of evidence that glycine receptor autoantibodies are pathogenic in PERM were the clinical observations that some patients improve with immunotherapies that lower circulating antibodies and that antibody titers correlate with clinical improvement and relapses in some cases (43; 64). Patients with PERM who are “seronegative” have a similar response to treatment as those patients with glycine receptor autoantibodies, suggesting that they too have pathogenic autoantibodies to as yet unknown CNS targets. On the other hand, patients with GAD65 antibodies seem to have a worse prognosis, though the numbers of patients in outcome studies is small (51).
Glycine receptor autoantibodies in PERM. Glycine receptors are pentameric ligand-gated chloride channels that exist as alpha homomers and alpha-beta heteromers, and their expression is spatially and developmentally regulated (49). In adults, alpha 1 heteromeric glycine receptors are the most abundant and are found on motor neurons in the spinal cord where glycine acts as an inhibitory neurotransmitter (11). Poisoning with strychnine, a potent antagonist of glycine receptors, causes profound (usually fatal) muscle rigidity as a direct result of loss of this spinal inhibition. Alpha 1 heteromeric glycine receptors are also found in the brainstem where glycinergic neurotransmission modulates eye movements; respiratory rhythms; and auditory, vestibular, and autonomic functions (33; 47; 79; 72; 71; 30). The alpha 3 subunit is also expressed in the spinal cord, particularly in the dorsal horns, and glycinergic neurotransmission here is involved in the processing of pain and itch (38; 29). Glycine receptors are extensively expressed in the retina where alpha subunits are restricted to specific retinal layers (81). Glycine receptors are found in the basal ganglia and forebrain, albeit at much lower levels, and probably located extrasynaptically (03). The physiological roles of glycine receptors in these brain areas remains poorly understood but in some regions they mediate tonic currents (54).
Glycine receptor autoantibodies from patients bind to the exposed extracellular domains of the 1-subunits in homomeric or alpha/beta heteromeric glycine receptors. Some patients’ sera additionally bind alpha 2 and/or alpha 3 glycine receptor subunits (12). Patients’ sera, but not that of healthy controls, contain antibodies that bind to neurons in sections of rat brainstem and ventral and dorsal horns of the spinal cord, where glycine receptors are most abundant. Because glycine receptor autoantibodies have been detected in cerebrospinal fluid as well as in serum, with substantial intrathecal synthesis in at least some cases, there is the potential for neurologic disease to arise as a direct result of modulation of the glycine receptor by autoantibodies. Antibody-mediated reduction or loss of glycinergic neurotransmission within the spinal cord and brainstem would be expected to result in hyperexcitability of motorneurons, hyperekplexia, cranial nerve dysfunction, disturbance of respiratory rhythms, and autonomic dysfunction accounting for many of the clinical features observed in patients with PERM (19).
The autoantibodies to glycine receptors found in patients are predominantly IgG1 subclass, with some IgG3 subclass. Divalent IgG1 can crosslink ionotropic receptors triggering their internalization and removal from the postsynaptic membrane in myasthenia gravis and anti-NMDAR encephalitis (39; 26; 41). Similarly, in HEK293 cells expressing glycine receptors, glycine receptor autoantibodies from patients are internalized, suggesting that these antibodies could also act by internalizing glycine receptors and thereby reducing the efficacy of inhibitory glycinergic neurotransmission (12). IgG1 and IgG3 antibodies are also capable of fixing complement and patient antibodies to glycine receptors have been shown to do this in vitro. However, it is not known whether complement activation in patients is responsible for any of the clinical manifestations. It seems unlikely that early disease is characterized by widespread neuronal destruction because MRI appearances are often normal and there is frequently a substantial response to immunotherapy.
A study directly showed a profound reduction of glycinergic neurotransmission in cultured motorneurons following incubation in IgG purified from patients with PERM and glycine receptor autoantibodies, providing the strongest evidence so far that these autoantibodies are pathogenic (20). The reduction in glycinergic currents was seen even after short incubations and when monovalent Fab fragments were used, suggesting that there are direct antagonistic actions of glycine receptor autoantibodies on glycine receptors in at least some patients. These conclusions are supported by studies demonstrating decreased potency of glycine on glycine receptors in the presence of patient autoantibodies (66).
The role of GAD65 autoantibodies in PERM. Autoantibodies to GAD65 are present in most patients with stiff-person syndrome and are found in a minority of patients with PERM (44; 17; 56; 12). GAD catalyzes the conversion of glutamic acid to GABA in GABAergic neurons. The GAD65 isoform is found at the cytoplasmic surface of synaptic vesicles and as such it is inaccessible to circulating antibodies in intact healthy neurons. Therefore, autoantibodies to GAD65 are unlikely to be the primary driver of stiff-person spectrum disorders. However, experiments using IgG from GAD65-antibody positive patients with stiff-person syndrome suggest the presence of pathogenic autoantibodies to other unknown CNS targets, which may affect inhibitory GABAergic neurotransmission (32; 15; 36; 82).
Interestingly, there is some evidence that the patients with GAD65 autoantibodies have a worse prognosis than those with glycine receptor autoantibodies or “seronegative” cases (51). It is possible that the presence of these antibodies is indicative of substantial neuronal damage with exposure of intracellular antigens to the immune system, although there are alternative explanations such as earlier diagnosis and more aggressive treatment of patients found to have glycine receptor autoantibodies.
DPPX autoantibodies. Antibodies from patients with anti-DPPX encephalitis bind to extracellular epitopes of DPPX, a modulator of the potassium channel, Kv4.2 (08). Kv4.2 and DPPX are widely expressed in the brain and enteric nervous system. A small study of anti-DPPX encephalitis reported lower DPPX and Kv4.2 expression in cultured neurons following 3-days incubation in a DPPX antibody positive patient IgG compared to control IgG, suggesting that antibody-dependent crosslinking and internalization of the entire Kv4.2 complex may occur. However, an increase in gut excitability within seconds of exposure to anti-DPPX serum has also been described, hinting at rapid pathogenic mechanisms not consistent with endocytosis of the Kv4.2 potassium channel (63). Although it seems likely that DPPX antibodies are pathogenic, given the strength of the clinical association and improvements seen with plasmapheresis and immunosuppressive treatments, the molecular mechanisms of this disorder have not yet been fully explored.
The role of glycine receptor autoantibodies in neurologic presentations other than PERM. Although the pathogenic actions of glycine receptor autoantibodies in PERM are well established, the role of glycine receptor autoantibodies in other neurologic disorders is less clear. Glycine receptor autoantibodies from individual patients all bind alpha 1 subunits but they have varying specificities for alpha 2 and alpha 3 subunits. However, this does not appear to account for different clinical presentations because there is no correlation between the subunit specificities and the clinical features in patients.
In stiff-person spectrum disorders and brainstem encephalitis, where the clinical presentation could be an anatomically limited variant of PERM, it seems likely that glycine receptor autoantibodies are pathogenic. Supporting this hypothesis, the frequency of clinical improvement with immunotherapy is high.
There are a growing number of reports and small case series of adult and pediatric patients with epilepsy occurring in association with glycine receptor autoantibodies including mesial temporal lobe, other focal epilepsies, and epileptic encephalopathies (28; 89; 78). A review of all glycine receptor antibody positive cases in the literature in 2018 (187 cases) identified 47.6% with PERM/stiff-person syndrome and 22.4% with epilepsy (74). However, the absolute number of cases reported remains small and those who have high titers of glycine receptor autoantibodies comprise a tiny fraction of all patients who present with seizures. Among these are patients who respond to standard antiepileptic treatment and others who have refractory seizures. A proportion of patients with refractory seizures respond partially or completely to immunotherapy (86; 05; 77; 27). Interestingly, some immunotherapy responsive patients have additional neurologic features such as dyskinesia or ataxia, and perhaps these additional signs are an important clue for an underlying autoimmune epilepsy syndrome (86; 77; 14). The pathogenic relevance of glycine receptor autoantibodies in epilepsy remains unclear at the time of writing – they could be a bystander phenomenon, indicative of an autoimmune process or perhaps themselves play a causative role in disease. However, it is worth reminding the reader that epileptic seizures are not typically observed in strychnine poisoning.
In other neurologic presentations, the response to immunotherapy has only been reported in a small number of cases but there appears to be a partial or complete response in at least some individuals.
Neuropathology. There are several reports documenting the findings in postmortem studies of patients with a clinical diagnosis of PERM. These describe perivascular lymphocytic cuffing and infiltration and a variable degree and distribution of neuronal loss in the brainstem and spinal cord, suggesting a cytotoxic T-cell mediated component to the disease. However, there are few pathological cases in the literature in which the autoantibody status of the patient was known. It is possible that the majority of the cases were anti-GAD65-positive, an antibody which is now associated with a less complete response to immunotherapy than glycine receptor autoantibodies, and may reflect less reversible pathology such as T-cell mediated cytotoxicity. Furthermore, the pathological changes in “end-stage” disease may not be representative of the pathogenic mechanisms earlier in the disease course.
A single case report documents the pathological findings in a young man with a clinical syndrome of PERM and retrospective finding of both glycine receptor and NMDAR autoantibodies in his serum (76). In common with the earlier postmortem studies, he had evidence of cytotoxic T-cell mediated neuronal injury. However, the interpretation of this finding is complicated by the presence of two likely pathogenic neuronal autoantibodies and the very rapidly fatal disease course, which is not typical.
Epidemiology
Most of the disorders associated with highly specific antibodies are rare, with only up to two new cases per million of the population. Glycine receptor antibodies are rarer still but the true incidence and prevalence are not known.
Prevention
There are no known prevention strategies for PERM or glycine receptor autoimmunity.
Differential diagnosis
Confusing conditions
The diagnosis of PERM, particularly at the early stages of disease when the clinical features are highly variable between patients, can be challenging. Indeed, it is not uncommon for a functional or psychiatric etiology to be suspected when patients first present. In other cases, alternative neurologic diagnoses may be considered, depending on the presentation; for example, myasthenia gravis in a patient with bulbar symptoms and/or complex ophthalmoplegia, or a focal dystonia in those with distal lower limb rigidity, or myelopathy in a patient with long tract signs and sphincter dysfunction. However, as the condition progresses a more classical syndrome usually emerges with elements of stiff-person syndrome, frequent autonomic involvement, and unequivocal brainstem signs.
PERM is differentiated from classical stiff-person syndrome by the rapid rate of progression and evidence of brainstem dysfunction (an exclusion criterion for classical stiff-person syndrome). Autonomic involvement may also be much more pronounced in those with PERM. A further clinical clue can be the anatomical distribution of muscle rigidity, which often affects the trunk and proximal lower limb muscles in classical stiff-person syndrome but more commonly affects distal muscles in PERM. Those with classical stiff-person syndrome usually have a more complete and sustained response to benzodiazepine treatment than those with PERM (57). Long tract signs and sensory symptoms/signs, except hyperreflexia without extensor plantars, are generally absent in classical stiff-person syndrome. Sphincter involvement should also point away from a diagnosis of classical stiff-person syndrome but can occur in PERM (though other causes of myelopathies should also be excluded).
Some patients with Creutzfeldt-Jakob disease may present with a rapidly progressive neurologic syndrome with similarities to PERM. Neuronal autoantibodies, including to glycine receptors, have been reported in a few cases of pathologically confirmed Creutzfeldt-Jakob disease but these are of low titer (68). Other investigations are extremely helpful in confirming the clinical suspicion of Creutzfeldt-Jakob disease including MRI, which usually has classical abnormalities on FLAIR and DWI sequences in Creutzfeldt-Jakob disease, and CSF for the RT-QuIC assay, which is highly sensitive and specific for Creutzfeldt-Jakob disease (70).
Poisoning with strychnine, a potent glycine receptor antagonist, can produce a similar clinical picture to PERM but it usually develops very quickly (within 5-30 minutes of ingestion) and is often fatal within hours. In some parts of the world, strychnine is used as a pesticide against small vertebrates such as rats, and this can be a source of accidental ingestion or inhalation (42).
Tetanus as a result of ingestion of the toxin produced by Clostridium tetani can also produce symptoms that overlap with PERM. Affected individuals develop muscle stiffness (classically trismus but also stiffness of the neck, back, and extremities), stimulus-sensitive spasms, dysphagia, seizures, and autonomic dysfunction. Difficulty with mouth opening has been reported in several cases of PERM with glycine receptor autoantibodies in the literature (24; 48). Tetanus occurs almost exclusively in those who have never been vaccinated or who have not had the required booster vaccinations, and who have sustained a wound through which Clostridium tetani (commonly found in soil) enters. From exposure to symptoms usually takes 3 to 21 days. There are no routine laboratory tests for tetanus and the diagnosis is usually made based on the history in combination with the clinical features. As in PERM, EMG may show continuous discharge of motor subunits. The differentiation of PERM from tetanus in patients who are at risk of tetanus remains challenging. The clue to a diagnosis of PERM can be the lack of response to standard treatments for tetanus (80).
In patients receiving treatment with antipsychotics, the symptoms of neuroleptic malignant syndrome may overlap with the clinical features of PERM (87). Classically patients with neuroleptic malignant syndrome develop “lead pipe” rigidity in all muscle groups with hyporeflexia, hyperpyrexia, diaphoresis, autonomic instability, and altered mental status. Seizures can occur in both disorders. In contrast to PERM, neuroleptic malignant syndrome typically resolves relatively rapidly on withdrawal of neuroleptics (rarely lasting beyond a month) but seizures, which are difficult to control with antiepileptics, are more likely to occur in PERM than neuroleptic malignant syndrome. Similarly, serotonin syndrome could be mistaken for a variant of PERM. Patents with serotonin syndrome usually have increased tone in the lower extremities, clonus, and hyperreflexia as well as hyperthermia, hypertension, tachycardia, tachypnea, diaphoresis, dilated pupils, and altered mental status. This condition rapidly resolves upon stopping the selective serotonin reuptake inhibitor.
Morvan syndrome is an autoimmune disorder associated with antibodies against CASPR2 (45). It comprises neuromyotonia with autonomic and CNS dysfunction and often insomnia and a characteristic sleep disorder, defined as agrypnia excitata, that encompasses severe insomnia, motor and sympathetic hyperactivity, and enacted dreams in the setting of loss of slow-wave sleep and the circadian rhythmicity of sleep (50). Neuromyotonia is a peripheral nerve hyperexcitability syndrome characterized clinically by muscle cramps and stiffness. However, neuromyotonia is readily differentiated from the rigidity seen in PERM on the basis of the characteristic EMG activity pattern (69).
Myotonic dystrophy type 1 may be adult-onset and clinical features include grip myotonia, slurring of speech, and difficulties with swallowing. In contrast to PERM, there is muscle weakness particularly affecting the face and upper/lower limb extremities as well as myotonia, which may be evaluated by percussion of the thenar eminence or forearm extensors. The EMG in myotonic dystrophy shows characteristic myotonic discharges (69).
Atypical parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, may also be in the differential for some patients presenting with PERM but the evolution of symptoms in progressive supranuclear palsy and multiple system atrophy is usually much longer in duration and more slowly progressive (survival 5-10 years). Moreover, those patients develop characteristic findings on MRI brain imaging (midbrain atrophy resulting in the “hummingbird” sign in progressive supranuclear palsy; iron deposition in the posteriolateral putamen, slit hyperintensity in the lateral aspect of the putamen on T2, and pontine atrophy resulting in the “hot cross bun” sign in multiple system atrophy). DAT scans may also show reduced striatal binding in multiple system atrophy (55).
In young children presenting with PERM, inherited disorders should be included in the differential. Children with hereditary hyperekplexia are usually most affected around the time of birth. In the most common forms of hereditary hyperekplexia (affecting the alpha 1 subunit of the glycine receptor), the generalized stiffness usually improves with age but the exaggerated startle reflex remains prominent throughout adulthood. This diagnosis is, therefore, straightforward to exclude on the basis of the history in all but the youngest patients (though the diagnosis of hereditary hyperekplexia is sometimes not made before adulthood). Brainstem signs are not observed in patients with alpha 1 glycine receptor mutations but complex neurologic phenotypes are seen in some patients with other mutations affecting glycinergic neurotransmission (GlyT2 and glycine receptor beta subunit mutations) (67; 16).
Myoclonus dystonia should be considered in young patients with slowly evolving myoclonus and dystonia but no other features of PERM. Though this condition is often autosomal dominant, there is rarely a suggestive family history because of maternal imprinting. Wilson disease can also have some overlapping features with PERM including dystonia, myoclonus, ataxia, and psychiatric/cognitive disturbance. It is important to exclude given it is a treatable disorder. For Wilson disease with neurologic complications 24-hour urinary copper and slit-lamp examination for Kayser-Fleischer rings are both highly sensitive.
In young patients with seizures, progressive myoclonic epilepsies should also be considered. In comparison to PERM, seizures are more prominent, ataxia occurs commonly, and rigidity is a later feature of disease. The EEG is often characteristic in progressive myoclonic epilepsies.
Subacute sclerosing panencephalitis is a rare complication of measles, usually occurring several years after the primary infection. Patients usually develop personality changes followed by seizures and myoclonus. After a few months, spasticity can develop as well as visual problems. The diagnosis is made of the basis of the history, suggestive EEG, and antimeasles IgG in the serum and CSF (31).
Diagnostic workup
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• PERM is a clinical diagnosis; CSF, MRI, EEG, and EMG may all be normal. | |
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• Detection of glycine receptor antibodies is important to confirm the autoimmune etiology of the disorder. |
In patients with a clinical syndrome that would fit with a diagnosis of PERM or stiff-person spectrum disorders, serum glycine receptor and GAD65 antibodies, CSF, neurophysiological studies, and MRI can be helpful in providing supportive evidence of an autoimmune etiology and excluding alternative diagnoses. However, it is worth noting in cases of PERM. In suspected cases a screen for underlying malignancies, particularly thymoma and lymphoma, should also be untaken, although most cases of PERM are not paraneoplastic.
Glycine receptor autoantibody testing. The test for glycine receptor autoantibodies is performed on live cells expressing glycine receptors. There has been considerable debate surrounding the relative sensitivity and specificity of serum versus CSF glycine receptor autoantibody testing, as for antibodies to other neuronal surface antigens. In retrospective cohorts, some patients have detectable glycine receptor autoantibodies in CSF but not in serum, but this has not been observed in prospective cohorts (17; 56; 12). Others have argued that CSF glycine receptor autoantibodies may be more specific for an antibody-drive neurologic disorder than serum autoantibodies. However, due to the restricted permeability of the blood-brain barrier to IgG, CSF antibodies are usually lower absolute titer than serum antibodies, even where there is evidence of intrathecal synthesis. Thus, it is likely that even where there are clinically relevant positive glycine receptor antibodies detected in serum, the CSF levels may be undetectable in some individuals.
In comparison to other neuronal autoantibodies, glycine receptor antibodies seem to be detected more frequently in patients with unrelated neurologic disorders or no neurologic disorder. One study including “neurologic disease controls” found that 6% had serum glycine receptor antibodies and they have been found in rare healthy controls at low titers (51). Furthermore, they have been detected in 20% of patients with lung cancer and a small proportion of individuals with thymoma without neurologic manifestations (02; 88). The relatively high frequency of glycine receptor antibodies in some studies of patients without neurologic disease may in part be accounted for by the methodologies used to detect glycine receptor antibodies, which vary between laboratories. An assay for glycine receptor modulating antibodies reported improved specificity for glycine receptor antibodies in stiff-person spectrum disorders over healthy controls who were positive on the conventional assay but remains technically challenging to perform and is not widely available (40).
We would advocate testing for glycine receptor antibodies in both serum and CSF undertaken in a laboratory with expertise in the detection of neuronal surface antibodies and interpreting the results in the clinical context of the patient. A positive glycine receptor autoantibody result from the serum or CSF is likely to indicate an autoimmune antibody-driven disorder in patients with stiff-person spectrum disorders and perhaps in other related presentations such as brainstem predominant encephalitis. However, in other neurologic disorders the clinical significance of glycine receptor autoantibodies has not been established, although some of these patients also improve with immunotherapies.
Although a positive glycine receptor antibody result is helpful in diagnosing patients with PERM, and titers within an individual patient appear to correlate with clinical improvements and relapses, it is unclear whether serial measures of glycine receptor autoantibody titers are helpful in guiding the clinical management of patients.
Other blood tests. In addition to checking for the presence of glycine receptor autoantibodies, serum may also be assayed for the presence of GAD65 antibodies. In those with prodromal gastrointestinal symptoms, DPPX antibodies should also be sent. Traditional paraneoplastic antibodies (anti-Ri, antiamphiphysin, etc.) if positive suggest an underlying malignancy, though seronegative, glycine receptor antibody positive and anti-GAD65 positive PERM may also be paraneoplastic.
An infectious screen, including HIV testing and hepatitis screening is advisable, particularly because treatment may involve immunosuppression. In stiff-person syndrome presentations, Borrelia serology should also be performed. A screen for other organ-specific (eg, thyroid peroxidase antibodies TPO) and nonorgan specific autoantibodies (eg, ANA) may provide evidence of a propensity towards autoimmunity. Hematological investigations (serum protein electrophoresis, paraprotein quantification, Bence-Jones protein) may provide evidence of underlying lymphoma. Patients may also have elevated serum creatine kinase due to excessive muscle contraction.
Other CSF tests. Examination of the CSF may provide supportive evidence of an inflammatory/autoimmune process and is also important to exclude infectious pathology and Creutzfeldt-Jakob disease. The CSF is abnormal in approximately 50% of patients with glycine receptor autoantibodies (usually with mild pleocytosis, mildly raised protein levels, and/or oligoclonal bands) (12; 06). Gram-stain, viral PCR, and RTQuIC are helpful to exclude infectious diseases and Creutzfeldt-Jakob disease, respectively.
Imaging. Brain MRI is often normal in PERM or may show unrelated abnormalities such as cerebral atrophy in older patients. Occasionally there are white matter lesions, temporal lobe inflammation, or other FLAIR abnormalities (12). DWI sequences are particularly helpful in the differentiation between PERM and Creutzfeldt-Jakob disease (70; 84). Fewer data are available for spinal cord MRI, but as for brain imaging, spinal imaging can be normal in cases of PERM/other neurologic disorders with glycine receptor autoantibodies. Occasionally short or patchy lesions or more rarely longitudinally extensive lesions are seen. Spinal imaging is particularly helpful in the exclusion of other myelopathies including compressive lesions.
A malignancy screen should be undertaken in most if not all patients presenting with PERM. Body CT and/or whole-body PET can be used and were found to be abnormal in 5 of 20 patients in one series (12).
Neurophysiology. EEG can be normal but often shows slow activity in keeping with an encephalopathic illness. In some cases epileptic discharges are seen, which help to guide symptomatic treatment.
EMG can be used to look for evidence of stiff-person syndrome, namely continuous motor activity in affected muscles despite attempts at relaxation, and cocontraction of agonist and antagonist muscles (12). However, these tests may also be within normal limits or affected by medications given to relieve muscle stiffness or spasms. EMG may also show abnormal stimulus-driven motor activity and a few reports have characterized the neurophysiological startle response to loud auditory stimuli by EMG recording in patients with PERM with glycine receptor autoantibodies (18). However, ideal recording conditions are rarely achievable in the hospital setting and normative data to facilitate the interpretation of the results are lacking.
Management
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• Initial treatment includes corticosteroids sometimes associated with plasmapheresis or intravenous immunoglobulins. | |
|
• Symptomatic treatment is important to ameliorate muscle spasms and hyperekplexia. |
There have been no clinical trials in patients with PERM. Broadly, the treatment of PERM is directed at suppressing the pathological immune response while controlling the symptoms and providing supportive treatment as required.
Symptomatic treatments. Benzodiazepines are considered first line treatment for muscle rigidity and spasms. Doses are titrated upwards according to the symptoms, with high doses often required due to the development of tolerance and progression of the disease. Side effects of excessive sedation and respiratory depression can limit the utility of these medications in clinical practice. Diazepam (5-100 mg/day in divided doses every 3-6 hours) is the most commonly used. Oral baclofen (starting at 5-10 mg/day and increasing to 40-60 mg/day) may also be helpful but sedation and cognitive side effects can limit the dose. In a few cases where long-term rigidity causes pain and disability intrathecal baclofen has been used (12; 73).
For hyperekplexia, clonazepam is a common choice, as in hereditary hyperekplexia (1.5-6 mg per day in three divided doses). The use of antiepileptics for the symptomatic treatment of myoclonus has also been reported in PERM, including levetiracetam, sodium valproate and carbamazepine, though with limited success.
Seizures, if they occur, are treated according to local guidelines, with no special precautions attributable to PERM/glycine receptor autoantibodies. In some cases, seizures are difficult to treat and require multiple agents at high doses (89).
Immunomodulatory treatment. A common approach to immunotherapy is to start with high dose corticosteroids, for example intravenous methylprednisolone (1 g daily for 3 days) followed by prednisolone (1 mg/kg up to 60 mg daily). Prophylaxis for gastric ulceration should be administered. If the course of treatment is prolonged, treatments to reduce cardiovascular risk and osteoporosis should also be considered. Side effects and complications of short-term corticosteroid use include hyperglycemia, hypertension, peptic ulceration, insomnia, and mood disturbance. Long-term consequences include diabetes, osteoporosis, skin changes, cataracts, and glaucoma. There is also a small but significant risk of avascular necrosis, particularly of the femoral head. Due to the long-term side effects, patients requiring prolonged immunosuppression (ie, those with relapsing disease) are usually switched to a steroid-sparing agent.
Because most patients follow a rapidly progressive and life-threatening course, those who do not have a rapid clinical response to intravenous methylprednisolone go on to receive further treatment with plasmapheresis (5 exchange treatments delivered over 5-10 days) and/or intravenous immunoglobulins (2 g/kg over 5 days). There have been no studies of the relative efficacy of these treatments and the choice is determined by local availability of plasmapheresis as well as patient factors affecting tolerability. The complications of plasmapheresis relate to the requirement for venous access (vascular injury, line sepsis), use of plasma and blood products (infusion reactions, anaphylaxis), as well as hemodynamic stresses, electrolyte imbalance (particularly hypocalcemia), and coagulopathies (resulting from the removal of clotting factors). Infusion reactions with intravenous immunoglobulins are relatively common and anaphylaxis can also occur. Other side effects include arterial and venous thromboembolic events and aseptic meningitis.
Plasmapheresis and intravenous immunoglobulin treatments may be repeated depending upon the clinical response and additional immunotherapies have also been used in the acute phase of PERM to induce remission, including cyclophosphamide or rituximab (12). Patients who relapse following initial treatment are usually retreated as above, and longer-term immunosuppressants are started such as rituximab (6-monthly), azathioprine, mycophenolate, or cyclosporin (12).
In the minority of patients with PERM in whom a malignancy is found, treatment of the cancer is considered necessary for amelioration of the neurologic disorder, as in other paraneoplastic neurologic syndromes (18; 07; 60; 61).
Supportive care. In the acute stages of PERM, patients are at risk of life-threatening ventilatory failure and severe autonomic disturbance (09; 12). There are several reports in the literature of deaths even among inpatients with PERM due to a failure to recognize these catastrophic complications. For this reason, treatment is best undertaken with close monitoring in a high-dependency environment. Due to bulbar failure many patients require artificial nutritional support via a nasogastric tube or percutaneous gastrostomy.
Further complications can arise due to prolonged immobility. Venous thrombo-embolic prophylaxis should be considered in immobile patients, particularly those receiving immunotherapies that further increase the risk. Physiotherapy, sometimes supplemented by botulinum toxin injections, is important in the prevention of contractures in patients who remain immobile for prolonged periods of time. Optimal recovery from PERM requires prolonged periods of specialist rehabilitation.
Outcomes
Case series of glycine receptor antibody positive patients with PERM suggest a clear, if often incomplete, response to immunotherapies in many individuals. The response can be slow (weeks to months) and prolonged periods of intensive rehabilitation may also be required. Among 33 patients reported by Carvajal-Gonzalez and colleagues, 27 improved on the modified Rankin scale (only one of whom was untreated), though only four recovered completely (12). A further two patients progressed and four patients died (two of these did not receive immunomodulatory therapy). Similar results were obtained by Martinez-Hernandez and associates, who reported that of 11 patients with stiff-person syndrome-plus and glycine receptor autoantibodies, eight improved, two stabilized, and one died (51). Even after immunomodulatory therapy a substantial proportion of patients suffer at least one further relapse of their disease (56; 12; 51).
Interestingly, patients who were antibody negative had a similar prognosis whereas those with GAD65 antibodies appeared to have worse outcomes, though the numbers were small. A case series of glycine receptor antibody positive patients with a variety of clinical presentations reported progressive disease in some patients despite immunotherapy (65).
Special considerations
Pregnancy
There are no case reports of patients who have had PERM in pregnancy.
Anesthesia
There is a single case report of general anesthesia in the context of PERM with glycine receptor antibodies (62). In this case sevoflurane was used without any reported adverse events. From the stiff-person syndrome literature (but not specifically those patients with glycine receptor autoantibodies) there are conflicting reports of prolonged hypotonicity resulting in prolonged intubation with sevoflurane and neuromuscular blockers, particularly in patients concurrently taking baclofen (13). Many of the cases of PERM with glycine receptor autoantibodies reported in the literature have described patients intubated and managed in intensive care, with no reported adverse reactions to anesthetic agents.
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
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Sarah J Crisp MBBChir PhD
Dr. Crisp of University of Cambridge has no relevant financial relationships to disclose.
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Angela Vincent MBBS
Dr. Vincent of Oxford University received royalties from Euroimmun AG as an inventor and lecturer fees from Lundbeck and UCB.
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Editor
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Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Patient Profile
- Age range of presentation
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- 1 months to 65+ years
- Sex preponderance
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- Female = male
- Heredity
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- None
- Population groups selectively affected
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- None
- Occupation groups selectively affected
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- None
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