Introduction
NSAbs and their clinical features
Antibodies directed against proteins involved in excitatory neurotransmission
NMDAR
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA-type (glutamate receptor)) receptor
Antibodies to proteins involved in inhibitory neurotransmission
GAD
Glycine receptor
GABA B receptor
GABAA receptor
Antibodies directed against ion-channel-associated proteins and cell adhesion proteins
Voltage-gated potassium channel (VGKC) complex
LGI1
NMDAR | LGI1 | CASPR2 | GAD1
| GlyR | GABAB
| |
---|---|---|---|---|---|---|
Median age of onset | 57 (19–80) [39] | 23 (17–66) [21] | 50 (1–75) [27] | |||
Gender | Equal [4] | F > M ~80 % [21] | Equal [27] | Equal [25] | ||
Clinical features | Frequent stereotyped progression from early cognitive dysfunction, psychiatric features and seizures, to later movement disorder, autonomic failure and reduction in consciousness [8] | FBDS LE [50] Often present in Morvan’s syndrome (coexisting with CASPR2-antibodies). Isolated epilepsy in some [59] | Morvan’s syndrome Neuropsychiatric features, insomnia, autonomic failure and neuromyotonia (often with LGI1 antibodies) [39, 107] Around 10 % have a cerebellitis [48] Isolated epilepsy noted (Irani unpublished) | Stiff person syndrome > cerebellar ataxia > LE > isolated epilepsy [19] | Stiff Person syndrome spectrum of diseases: PERM > vSPS > cSPS [27] Rarely LE [27] | Rarely cerebellar ataxia, status epilepticus or opsoclonus myoclons—usually progresses to LE [108] |
Investigation findings | LP Normal [45] EEG abnormal in 80 % | LP abnormal in 50 % [39] EEG abnormal in ~60 % if central involvement [107] | MRI abnormal in 100 % (used as selection criteria in this study) [21] LP abnormal in 22 % [21] | MRI Head abnormal in 30 %, spine in 20 % [27] LP abnormal in 60 % [27] EMG abnormal 60 % [27] EEG abnormal in 70 % [27] | MRI abnormal in ~75 % [25] LP abnormal in 60 % [25] EEG abnormal in ~90 % [25] | |
Tumour association | 6 % in <12-year olds [5] | Thymoma ~40 % of Morvan’s [39] Tumour <10 % in other presentations [107] | None [21] | Thymoma <10 % [27] | ||
Immunotherapy efficacy | Poor efficacy—0 % seizure freedom [21] | 90 % shows good response [27] | ||||
Prognosis (inc relapses) | 6 % mortality (12 % if untreated) [5] | 2 % mortality [4]; low rates of relapse unless treatment is withdrawn early | 20–31 % mortality, (highest risk if thymoma) | Low mortality, due to poor response to Rx, relapse not able to be defined [21] | 10 % mortality (highest risk if thymoma) [27] 11 % relapse rate [27] |
AMPAR | AQP4 | MOG | GABAA
2
| DPPX | IgLON5 | |
---|---|---|---|---|---|---|
Median age of onset | 60 (38–87) [16] | 37 (4–78) [106] | 37.5 (3–70) [106] | 22 (3–63) [28] | 59 (52–76) [70] | |
Gender | F > M ~90 % [16] | F > M (90 %) [106] | M > F (60 %) [106] | M > F (80 %) [28] | Equal [70] | |
Clinical features | LE | NMOSD | NMOSD—more likely to have optic neuritis, especially bilaterally [106] | Status epilepticus or epilepsia pars continua at high titres [28] LE [37] | REM and non-REM sleep disorder, sleep breathing disorder, movement disorder. Occasional rapid brainstem degeneration with dysautonomia, central hypoventilation, dysphagia and dysarthria [70] | |
Investigation findings | MRI abnormal in 80 % [16] LP abnormal in 90 % [16] EEG abnormal is 60 % [16] | MRI abnormal 60 % [106] LP oligoclonal bands in 20 % [106] | MRI abnormal 40 % [106] LP oligoclonal bands in 0 %, more likely to have higher cell count [106] | MRI abnormal in 100 % [28] LP abnormal in 84 % [28] EEG abnormal 100 % [28] | MRI abnormal in 66 % [68] EEG abnormal in 100 % [68] LP abnormal in 100 % [68] | Videopolysomnography—OSA, stridor and abnormal sleep architecture Neuropathology—neuronal loss and atypical brainstem tau deposition [70] |
Tumour association | Lung, breast, thymoma ~70 % [16] | Rare, various infections can trigger relapse | None | 16 % treated for Hodgkin’s lymphoma 10 months previously [28] | None | None |
Immunotherapy efficacy | 90 % response rate to IT ± oncological therapy. [16] | Immunoresponsive [106] | 50 % recovery with IT [28] | 100 % gradual response to IT [68] | No response to immunotherapy [70] | |
Prognosis (inc relapses) | 30 % mortality (higher if tumour and no treatment) 50 % relapse rate (median time to relapse 16 months) [16] | 70 % have relapsing course [112] | 50 % relapse (4.5 year median follow up) [106] | Mortality 33 % [28] 16 % relapse [28] | No mortality 100 % relapse rate off IT [68] | Progressive |
CASPR2
Other VGKC-complex proteins
Dipeptidyl-peptidase-like protein-6 (DPPX)
IgLON5
Pathogenic considerations
LGI1-animal mutant | LGI1-human mutant | NMDAR-animal mutant | NR1 human polymorphism | NMDAR—drugs, e.g. ketamine/phencyclidine | CASPR2-animal mutant | CASPR2-human mutant | GABAB1R drugs—baclofen | GABAB1R animal mutant | GABAB1R human polymorphism | |
---|---|---|---|---|---|---|---|---|---|---|
Cognitive | Not specified | Unaffected interictally [113] | Impaired memory [78] | Associated with nonsyndromic intellectual disability [114] | Behavioural inflexibility, communication and social ability impairment [91] | Intellectual disability, inattention [93] | Impaired visual learning [79] | N/A | ||
Psychiatric | Inactivity, slow walking [84] | Unaffected interictally [113] | Anhedonia, anxiety, psychomotor agitation [78] | Hyperactivity, severe agitation, psychosis [115] | Hyperactivity and repetitive behaviour [91] | Hyperactivity, aggression, autism [93] | No effect on anxiety [79] | N/A | ||
Seizures and semiology | Homozygous null mice myoclonic seizures [84] | Brief aphasic seizures with auditory hallucinations, nocturnal tonic–clonic seizures [87] | None noted | de novo mutation found in childhood epileptic encephalopathy [121] | Seizures reported rarely [122] | Seizures reported after 6 months of age [91] | Frequent, intractable predominantly focal seizures often with secondary generalisation [93] | Seizures [123] | Association to temporal lobe epilepsy [81] | |
Other features | Null mice die at 12–18 days [84] | NMDA null mice die of severe hypoventilation [77] | N/A | Normal nerve conduction studies with no evidence of hyperexcitability [90] | N/A | Impaired locomotion [79] | N/A | |||
Neuronal abnormalities | Not specified | Disinhibition of cortical excitatory neurons and reduced neuronal synchrony [78] | N/A | Impaired synaptic plasticity [115] | Widespread cortical dysplasia [93] | N/A | Null mice have histologically normal brains [117] | N/A |