In 1976, Whiteley et al. first described this disease[5]. He reported two patients who presented with encephalomyelitis associated with subacute myoclonic spinal neuronitis and stiff person syndrome (SPS), which had been categorized as stiff-person spectrum disorders (SPSD) and was later identified to be progressive encephalomyelitis with rigidity and myoclonus (PERM). PERM is an underrecognized and rare childhood disease. In 2013, Joana Damásio described the first pediatric case of PERM[6]. So far, only nine cases of PERM have been reported in children worldwide, including our case. As people learn more about the disease, it is found that PERM has a variety of symptoms upon onset. The main clinical manifestations include rigidity, stiff spasms of the trunk and limb muscles, symptoms of brainstem spinal cord, deep and shallow sensory disturbances, and autonomic symptoms.
The diagnosis of PERM is very challenging, which is primarily clinical. In 2022, Newsome and Johnson proposed the diagnostic criteria of all SPS-spectrum disorders, which includes classic, partial, pure cerebellar ataxia, SPS-plus, and PERM. They proposed examples of extended diagnostic criteria for PERM[7]: 1. Major criteria: (1) Clinical presentation including typical body regions involved (neck, torso, extremities, brainstem and/or cerebellar symptoms); (2) Hallmark triggers for spasms/increased rigidity (including abrupt loud noises, cold weather, open spaces, emotional stress (good and bad), and/or tactile stimuli); (3) Exam findings: admixture of other phenotype findings plus encephalopathy and severe torso rigidity and/or myoclonus (multifocal or generalized); (4) Presence of serum autoantibody to glutamic acid decarboxylase 65-kilodalton isoform (GAD65) (high titer), glycine receptor, or amphiphysin; (5) EEG (generalized slowing and/or epileptic discharges); (6) Exclusion of alternative diagnoses and no better explanation for syndrome; 2. Minor criteria: (1) Autonomic dysfunction; (2) Presence of CSF autoantibody to GAD65, glycine receptor, or amphiphysin; (3) CSF pleocytosis; (4) CSF-restricted oligoclonal bands; (5) EMG demonstrating co-contraction of agonist and antagonist muscles and/or continuous motor unit activity in affected muscles (paraspinal/abdominal musculature and/or legs/arms); (6) Brain MRI demonstrates T2/contrast-enhancing lesion(s) in brainstem; (7) Brain fluorodeoxyglucose (FDG)-positron emission tomography demonstrates hyper-or-hypometabolism within cortices.
The patient we reported initially experienced abdominal pain and skin itching, with gradual worsening of his condition, followed by truncal and limb rigidity, spasms of the trunk and limb during sleeping, deep and shallow sensory disturbances, dysuria, and dysphagia. His disease acutely began possibly due to infection and exacerbations. The clinical response fluctuated despite immunotherapy but showed persistent clinical improvement after a stronger immunotherapy treatment.
The common differential diagnoses of PERM syndrome include tetanus, psychogenic dyskinesia, and neuromyotonia (NMT). The typical symptom of tetanus is opisthotonus. It can be identified by the medical history, typical clinical manifestations, no response to benzodiazepines, and no relief during sleep. The main clinical features of psychogenic dyskinesia are sudden onset and sudden cessation. It can be identified by electromyography, and placebo treatment is effective. The main feature of neuromyotonia is when muscle stiffness cannot be relieved during sleep. There is no response to benzodiazepines.
The etiology of PERM is unknown, which may be relevant to immunity. GlyRAb is thought to be associated with 70% of cases with PERM, other antibodies (including anti-amphiphysin (16%), anti-GAD, and anti-DPPX) are also associated with PERM, and 13% were seronegative[8]. A recent retrospective analysis found that GlyR antibodies were associated with obvious brainstem, autonomic, and sensory symptoms. Patients with anti-GAD experience sporadic progressive ataxia, palatal myoclonus, and epilepsy. Patients with anti-DPPX have obvious eye movement disorders and gastrointestinal symptoms[9]. Since our patient’s serum and CSF related antibodies (GlyR antibodies, DPPX antibodies, GAD antibodies, NMDAR antibodies) were negative, we performed tissue-based assay with peripheral blood. Positive cell-like fluorescence could be seen in neuronal dendrites of the hippocampus and cerebellum’s Purkinje cells. We did not have the ability to complete the cell-based assay. At the same time, our patient simultaneously had antithyroid peroxidase antibody and antithyroglobulin antibody, which suggested the involvement of immune dysfunction. Studies have found that PERM was closely related to other autoimmune diseases such as thyroid disorders and diabetes[10]. Therefore, our patient requires monitoring for the development of potential autoimmune disease. Further investigation is needed to clarify the mechanism of interaction between these antibodies. Different immune specificities may indicate distinct underlying disease mechanisms and underpinnings which may explain some of the changes in clinical phenotype.
So far, only nine cases of PERM have been reported in children worldwide, including our case. We summarized the currently reported pediatric PERM cases in Table 1. We found that there were more females than males, and the cause for this discrepancy is unclear. The age of onset ranged from 14 months to 18 years, with an average age of 14 years. Patients were generally older, with heterogeneous clinical features. All patients had onset of stiffness and spasms. Brainstem symptoms were present in 78% of patients. Autonomic abnormalities and cognitive impairment occurred in 44% of patients.
Although the incidence of dysautonomia was not high, if not closely monitored, severe respiratory failure may occur, and patients must be transferred to the intensive care unit for management. A quarter of patients required tracheal intubation and the mortality was as high as 40%[2]. We found GlyR antibodies, GAD antibodies, DPPX antibodies, VGKC-complex antibodies in patients with PERM, which was similar to adult cases.
So far there is no consensus on the treatment recommendations of PERM, which mainly consist of immunotherapy and symptomatic treatment, similar to treatment for adults[7, 8, 11, 12]. Newsome and Johnson proposed an upgraded approach to immunotherapy[7]: (1) IVIG, corticosteroids, or plasma exchange; (2) plasma exchange, rituximab, mycophenolate mofetil, azathioprine, or a combination of therapies; (3) cyclophosphamide or a combination of therapies; (4) stem cell therapy. If the patient is experiencing acute exacerbations during the treatment of symptoms, then immunotherapy should be considered. If the patient does not respond to the above treatments, escalating to a stronger immunotherapy should be appropriate to consider. It is recommended to start immunotherapy within two months of onset[8]. There is little literature on the long-term prognosis of PERM. 18% of patients experienced a chronic disease course and acute exacerbation. Residual sequelae and recurrence are common. The time to relapse varies, ranging from a few weeks to nine years after onset[13]. Long-term follow-up is crucial for disease management. Our patient did not display the relevant antibodies that have been reported so far. He presented acutely and had periods of exacerbation. Treatment response tended to fluctuate during the acute disease phase. He demonstrated a significant response to the combined escalation approach of immunotherapy: IVIG, corticosteroids, plasma exchange, and rituximab, and displayed consistent improvement later. So far, this patient has no recurrence. The reason why our patients responded poorly to initial treatment was not yet clear. Some studies found that the seronegative group had a poor response, with only 18% of patients having a substantial response and 9% having a partial response. However, no recurrence occurred in this group[8].
All current pediatric cases were reported in this study in order to increase the awareness of this disease among pediatricians. Overall, PERM is a rare disease that requires a combination of signs and symptoms as well as accessory examination to diagnose. Early diagnosis is important for the health of children with PERM because treatment with symptomatic management and immunotherapy may help save lives and improve long-term prognosis. Pediatricians need to be familiar with the clinical manifestations of the disease in order to initiate appropriate treatment.