Table E-1 (A). Clinical Features of Patients with Axonopathic PNH

Table e-1 (a). Clinical features of patients with axonopathic PNH.

Classifica-tion / Sex / Age at onset / Clinical auto-immunity / Familial auto-immunity / Motor symptoms / Sen-sory symptoms / Hyper-hidrosis/
Dys-autonomic symptoms / CNS symptoms / Other neurologic symtpoms / Course (disease dura-tion) / Treat-ments employed
Territory / Myokymia / Cramps / Worsened with exercise / Weakness / Hyper-trophy / Tendon reflexes
1 / Prion Disease / M / 55 / No / No / F, L, T / ++ / No / Yes / No / No / Brisk / No / No/Yes / Yes / Dementia, Chorea, Ataxia* / Subacute
(6 mo) / -
2 / Diabetic Neuropathy / M / 65 / No / No / L / +* / + / Yes / Yes, distal / No / Achillean Absent / Yes / No/No / No / No / Chronic but fading
(5 ys) / CBZ, PGB
3 / Copper Deficiency / M / 33 / No / No / L, T / + / + / Yes / Yes, distal* / No / Absent / Yes / No/No / No / No / Chronic progressive (12 ys) / CBZ
4 / Monomelic Amyotrophy / M / 38 / Psoriasis / Yes (psoriasis) / F, L / ++* / + / Yes / Yes, distal / No / Absent in URL, others brisk / No / No/No / No / No / Chronic progressive (3 ys) / -
5 / MGUS / M / 50 / No / No / L, T / ++ / ++* / Yes / No / No / Absent / Yes / No/No / Yes / Postural tremor / Chronic progressive (8 ys) / GBP
6 / MMN / M / 34 / MMN / No / F, L / ++ / ++ / Yes / Yes, distal, asymmetric* / No / Absent / Yes / No/No / No / No / Chronic progressive (8 ys) / GBP, PGB
7 / Axonopathic PNH / M / 18 / No / No / F, L, T / + / ++* / Yes / No / Yes / Normal / No / Yes/Yes / Yes / Chronic headache / Chronic but fading
(13 ys) / OXC,
8 / Axonopathic PNH / F / 35 / No / No / L, T / No / + / Yes / No / No / Absent / Yes / No/Yes / No / Ataxia* / Chronic progressive (2 ys) / -
9 / Axonopathic PNH / M / 35 / No / No / L / ++ / +* / Yes / Yes, distal / No / Normal / Yes / No/No / No / No / Chronic but fading
(7 ys) / -
10 / Axonopathic PNH / F / 57 / No / No / L / No / +* / Yes / No / No / Normal / No / No/No / No / No / Chronic but fading
(7 ys) / GBP, PGB
11 / Axonopathic PNH / M / 43 / Oligoarthritis and Raynaud / No / L, T / ++ / ++* / Yes / Yes, distal / Yes / Hypoactive, Achillean absent / Yes / No/No / Yes / Chronic headache, Episodic dizziness, RLS / Chronic progressive (7 ys) / CBZ, PGB, IvIg
12 / Axonopathic PNH / M / 45 / No / No / L, T / No / +* / Yes / No / No / Normal / Yes / No/No / No / No / Chronic but fading
(7 ys) / CBZ, GBP
13 / Axonopathic PNH / M / 55 / No / No / L / ++ / +* / Yes / No / No / Normal / Yes / No/No / Yes / No / Chronic progressive (6 ys) / CBZ, GBP
14 / Axonopathic PNH / M / 30 / No / No / F, L, T / ++ / ++* / Yes / Yes, distal / No / Normal / Yes / No/No / Yes / Chronic headache / Chronic progressive (20 ys) / -
15 / Axonopathic PNH / M / 40 / No / No / L, T / ++ / +* / Yes / Yes, distal / No / Brisk / Yes / No/ Yes / Yes / Chronic headache, Episodic dizziness, Postural tremor / Chronic progressive (20 ys) / CBZ, GBP, LEV,
IvIg
16 / Axonopathic PNH / F / 30 / Thyroiditis / Yes (Raynaud) / L / No / ++* / Yes / Yes, distal / No / Achillean absent / Yes / No/ Yes / Yes / Chronic headache, Episodic dizziness / Chronic but fading
(15 ys) / CBZ
17 / Axonopathic PNH / M / 30 / Graft versus host diseasea / No / F, L, T / ++ / ++* / Yes / Yes, proximal / No / Normal / Yes / No/Yes / Yes / Episodic dizziness / Chronic progressive (3 ys) / GBP, IvIg, steroids, CyA, rituximab
18 / Axonopathic PNH / M / 32 / Inflammatory Bowel disease / No / F, L, T / ++ / +* / Yes / No / Yes / Normal / No / Yes/ Yes / No / No / Chronic but fading
(8 ys) / CBZ, GBP

Blue color: known cause. PNH: Peripheral Nerve Hyperexcitability. M: male F: female. MGUS: Monoclonal gammopathy of unknown significance. MMN: Multifocal motor neuropathy with conduction block. F: Face or cranial muscles. L: Limbs. T: Trunk. Cramps and Myokymia: No: Not present. +: present as a symptom. ++: present both as a symptom and as a sign during examination. *: Presenting complaint. URL: Upper right limb. CNS: Central nervous system. RLS: Restless legs syndrome. CBZ: carbamazepine; GBP: gabapentin; PHE: phenytoin; VPA: valproic acid; PGB: pregabalin; IvIg: intravenous immunoglobulin; CyA: cyclosporine

Table e-1 (b). Clinical features of patients with isolated PNH.

Classification / Sex / Age at onset / Clinical autoimmunity / Familial auto-immunity / Motor symptoms / Sensory symp-toms / Hyper-hidrosis/
Dysautonomic symptoms / CNS symptoms / Other neurologic symtpoms / Course (disease duration) / Treatments employed
Territory / Myokymia / Cramps / Worse-ned with exercise / Weakness / Hyper-trophy / Reflexes
19 / Paraneo-plastic / M / 74 / Thymoma, Myasthenia gravis, haemolytic anaemia / No / L / ++ / No / Yes / Yes, proximal* / No / Normal / No / No/No / No / No / Subacute
(1 mo) / Thymectomy
20 / Paraneo-plastic / F / 38 / Thymoma, Myasthenia gravis / No / L / ++ / No / Yes / Yes, proximal* / No / Normal / No / No/No / No / No / Chronic, relapsing remitting (4 ys) / Thymectomy IvIg and steroids
21 / Paraneo-plastic / M / 57 / Malignant thymoma, Myasthenia gravis / No / L, T / ++ / + / Yes / Yes,
Proximal* / No / Normal / No / No/No / Yes / No / Chronic, relapsing remitting (1 yr) / Thymectomy and chemotherapy
22 / Paraneo--plastic / F / 41 / Papillary thyroid cancer, No / No / L, T / ++ / +* / Yes / Yes, distal / No / Normal / No / No/No / No / No / Chronic but fading (6 mo) / Thyroid resection an radioactive I.
23 / Isolated PNH / M / 30 / Coeliac disesase / Yes (Thyroiditis) / L, T / ++* / No / Yes / Yes, distal / No / Normal / Yes / No/No / Yes / No / Chronic but fading (4 ys) / GBP
24 / Isolated PNH / F / 17 / Thyroiditis / No / L, T / No / +* / Yes / No / No / Normal / No / No/No / No / No / Chronic but fading (25 ys) / CBZ, GBP, PGB
25 / Isolated PNH / M / 46 / Coombs positive haemolytic anaemia, Lung adenocarcinoma 6 years before PNH / No / L, T / + / +* / Yes / No / No / Achillean absent / Yes / No/No / No / No / Chronic but fading (7 ys) / GBP
26 / Isolated PNH / F / 47 / Thyroiditis / No / F, L, T / ++ / +* / Yes / No / Yes / Brisk / No / No/No / Yes / No / Chronic but fading (5 ys) / -
27 / Isolated PNH / M / 23 / Arthritis-Psoriasis / Yes (SLE, AS) / L, T / + / +* / Yes / No / Yes / Normal / No / No/No / Yes / No / Chronic but fading (4 ys) / GBP, CBZ
28 / Isolated PNH / M / 15 / Cutaneous vasculitis / No / F, L, T / ++ / +* / Yes / No / No / Normal / No / Yes/Yes / Yes / Postural tremor / Chronic progressive
(9 ys) / GBP, CBZ, IvIg
29 / Isolated PNH / F / 40 / Thyroiditis / Yes (Thyroiditis) / L, T / ++ / +* / Yes / No / No / Brisk / No / No/No / Yes / Chronic headache / Chronic but fading (9 ys) / CBZ
30 / Isolated PNH / F / 20 / Thyroiditis, autoimmune myocarditis / Yes (Thyroiditis) / L, T / + / +* / Yes / No / No / Normal / Yes / Yes/Yes / Yes / Chronic headache / Chronic but fading (30 ys) / -
31 / Isolated PNH / M / 60 / No / No / F, L, T / ++ / +* / Yes / Initially no, later, distal weakness / No / Normal / No / No/No / Yes
(Limbic encephalitis)* / No / Chronic but fading (5 ys) / IvIg, PHE
32 / Isolated PNH / F / 30 / Polyarthritis / Yes (RA) / F, L, T / ++ / +* / No / No / Yes / Normal / Yes / No/Yes / No / Episodic dizziness, Chronic headache / Chronic but fading (9 ys) / CBZ
33 / Isolated PNH / F / 17 / No / No / L / No / +* / Yes / No / No / Normal / No / No/No / Yes / No / Chronic progressive
(10 ys) / CBZ, GBP
34 / Isolated PNH / M / 29 / No / No / F, L, T / ++* / + / Yes / No / Yes / Normal / Yes / Yes/Yes / Yes / Chronic headache, Postural tremor / Chronic progressive
(18 ys) / PHE, CBZ, VPA
35 / Isolated PNH / M / 43 / No / No / F, L, T / ++ / ++* / Yes / No / No / Normal / No / No/Yes / No / No / Chronic progressive
(9 ys) / -
36 / Isolated PNH / F / 51 / No / No / L, T / + / +* / No / No / No / Normal / Yes / No/No / No / Episodic dizziness / Chronic but fading (5 ys) / GBP
37 / Isolated PNH / M / 21 / No / Yes (Polyarthritis) / L, T / + / +* / Yes / No / Yes / Normal / Yes / No/Yes / Yes / Chronic headache / Chronic but fading (2 ys) / GBP, CBZ, PHE
38 / Isolated PNH / F / 40 / Polyartrhitis / Yes (Thyoriditis, Polyarthritis) / F, L, T / + / +* / Yes / No / No / Normal / No / Yes/Yes / Yes / RLS / Chronic progressive
(16 ys)

PNH: Peripheral Nerve Hyperexcitability. M: male F: female. SLE: Systemic Lupus Erythematosus. AS: Ankylopoietic Spondylosis. RA: Rheumatoid arthritis. F: Face or cranial muscles. L: Limbs. T: Trunk. Cramps and Myokymia: No: Not present. +: present as a symptom. ++: present both as a symptom and as a sign during examination. *: Presenting complaint. CNS: Central nervous system. RLS: Restless legs syndrome; CBZ: carbamazepine; GBP: gabapentin; PHE: phenytoin; VPA: valproic acid; PGB: pregabalin; IvIg: intravenous immunoglobulins.

Table e-1 (c). Ancillary tests in patients with axonopathic PNH.

Classification / Immunofluorescence / VGKC Ab / Other autoantibodies / CK / Other ancillary tests / Spinal fluid / NCS / Afterdischarges / EMG / NMT discharges
1 / Prion disease / Negative / Negative / ANA (1/40) / Normal / Abnormal MRI: T2 hyperintensity in the basal ganglia / Mild raise in protein, No OCB, 14-3-3 present / Slightly decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / Yes
2 / Diabetic Neuropathy / Negative / Negative / Anti-PGC (1/640) / Normal / No / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No
3 / Copper deficiency / Negative / Negative / Negative / HyperCKemia
(200 - 500) / Muscle biopsy with mild myopathic signs, mitochondrial proliferaiton and mild denervation changes; Sural nerve biopsy with loss of small myelinated fibers; Low Copper. / Normal, No OCB / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No
4 / Monomelic Amyotrophy / Negative / Negative / Anti Smooth Ms (1/80),
Striational (1/32) / HyperCKemia (200-500) / No / Normal, No OCB / Normal / Yes / Neuropathic MU in cervical and lumbar territories; PSW and Fib in cervical region / No
5 / MGUS / Positive granular layer of the cerebellum / Negative / Striational (1/16) / HyperCKemia (>1000) / Muscle biopsy with inflammatory myopathy / Not done / Initially decreased amplitude in CMAPs, later also SNAPs / Yes / Neuropathic MU / No
6 / MMN / Negative / Negative / ANA (1/40),
Anti-GM1 / Normal / No / Normal, No OCB / Multifocal motor conduction blocks / No / Neuropathic MU / Yes
7 / Axonopathic PNH / Negative / Negative / Anti Smooth Ms (1/80) / HyperCKemia (>1000) / Muscle biopsy with mitochondrial proliferation and mild myopathic signs; Raised levels of lactic acid at rest. / Not done / Normal / No / Neuropathic MU / No
8 / Axonopathic PNH / Negative / Negative / Negative / HyperCKemia (500-1000) / Muscle biopsy with mitochondrial proliferation and mild myopathic signs; Achantocytes. / Mild raise in protein, No OCB / Decreased amplitude in CMAPs / Yes / Neuropathic MU / Yes
9 / Axonopathic PNH / Negative / Negative / Anti-Smooth Ms (1/80) / HyperCKemia (200-500) / No / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No
10 / Axonopathic PNH / Negative / Negative / Negative / Normal / No / Not done / Decreased amplitude in SNAPs and CMAPs / Yes / Neuropathic MU / Yes
11 / Axonopathic PNH / Negative / Negative / Negative / Normal / Skin biopsy with loss of small myelinated fibres. / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / Yes
12 / Axonopathic PNH / Negative / Negative / Negative / HyperCKemia (200-500) / No / Not done / Decreased amplitude in SNAPs and CMAPs; multifocal asymmetric / No / Neuropathic MU / No
13 / Axonopathic PNH / Negative / Negative / Negative / Normal / No / Not done / Decreased amplitude in CMAPs / No / Neuropathic MU / No
14 / Axonopathic PNH / Negative / Negative / Anti-Thyroid, Striational (1/16) / HyperCKemia (500-1000) / Muscle biopsy with denervation atrophy and mild myopathic changes / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No
15 / Axonopathic PNH / Negative / Negative / Negative / HyperCKemia (200-500) / No / Normal, No OCB / Normal / No / Neuropathic MU / Yes
16 / Axonopathic PNH / Negative / Negative / Anti-Thyroid, ANA (1/80) / Normal / No / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No
17 / Axonopathic PNH / Negative / Negative / Anti-PGC (1/80) / Normal / Muscle biopsy: inflammatory infiltrates akin to dermatomyositis / Not done / Decreased amplitude in SNAPs and CMAPs / No / Myopathic MU / Yes
18 / Axonopathic PNH / Negative / Negative / Negative / HyperCKemia (500-1000) / Muscle biopsy with mild myopathic signs / Not done / Decreased amplitude in SNAPs and CMAPs / No / Neuropathic MU / No

Blue color: known cause. PNH: Peripheral Nerve Hyperexcitability. VGKC Ab: Voltage-gated Potassium Channel Antibodies. CK: Creatine Kinesa. NCS: Nerve conduction studies. EMG: Electromyography. NMT: Neuromyotonic discharges. ANA: Anti-nuclear antibodies. PGC: Parietal gastric cell. Ms: Muscle MGUS: Monoclonal gammopathy of unknown significance. MMN: Multifocal motor neuropathy with conduction block. MRI: Magnetic resonance imaging. OCB: Oligoclonal bands. CMAPs: Compound muscle action potentials. SNAPs: Sensory nerve action potentials.MU: Motor units. PSW: Positive sharp-waves. Fib: Fibrillations

Table e-1 (d). Ancillary tests in patients with isolated PNH.

Classification / Immunofluorescence / VGKC Ab / Other autoantibodies / CK / Other ancillary tests / Spinal fluid / NCS / Afterdischarges / EMG / NMT discharges
19 / Paraneoplastic (Thymoma) / Negative / Negative / ANA (1/80), Striational (1/512) Coombs+, Anti-ACh receptor / Normal / Mediastinal tumour (thymoma) / Normal, No OCB / Decremental response / No / Normal / Yes
20 / Paraneoplastic (Thymoma) / Positive staining of hippocampus dentate gyrus and Purkinje cells / Negative / ANA (1/640), Striational (1/256), Anti-ACh receptor / Normal / Mediastinal tumour (thymoma) / Not done / Normal / Yes / Normal / Yes
21 / Paraneoplastic (Thymoma) / Positive nuclear staining / Negative / ANA (1/80), Striational (1/256), Anti-ACh receptor / Normal / Mediastinal tumour (thymoma) / Not done / Decremental response / Yes / Normal / Yes
22 / Paraneoplastic (Thyroid cancer) / Negative / Negative / Negative / Normal / Thyroid nodule (thyroid carcinoma) / Not done / Normal / Yes / Normal / Yes
23 / Isolated PNH / Negative / Negative / Anti-Gliadin / Normal / No / Not done / Normal / No / Normal / No
24 / Isolated PNH / Negative / Negative / Rheumatoid Factor, Anti Striational (1/16) / Normal / Muscle biopsy with mild myopathic signs. / Not done / Normal / Yes / Normal / No
25 / Isolated PNH / Positive mollecular layer / Positive (109) / Striational (1/16), Coombs positive / HyperCKemia (>1000) / Muscle biopsy with mitochondrial proliferaiton and mild myopathic signs. / Not done / Normal / No / Neuropathic MU only in lower limbs / No
26 / Isolated PNH / Positive diffuse staining / Negative / Anti-Thyroid / Normal / No / Not done / Normal / No / Normal / No
27 / Isolated PNH / Negative / Negative / Negative / HyperCKemia (200-500) / HLA-B27 / Not done / Normal / No / Normal / No
28 / Isolated PNH / Negative / Negative / ANA (1/80), Anti Smooth Ms (1/80) / Normal / No / Not done / Normal / Yes / Normal / No
29 / Isolated PNH / Negative / Negative / Anti-Thyroid, ANA (1/40) / Normal / No / Normal, No OCB / Normal / Yes / Normal / Yes
30 / Isolated PNH / Negative / Negative / Negative / Normal / No / Not done / Normal / No / Normal / No
31 / Isolated PNH / Positive neuropil and mollecular layer / Positive (3493) / ANA (1/640) / Normal / No / Mild raise in protein, OCB / Initially normal, later decreased amplitude in CMAPs / No / Initially normal, later Neuropathic MU, PSW and Fib / Initially No, later Yes
32 / Isolated PNH / Negative / Negative / ANA (1/40) / Normal / No / Not done / Normal / No / Normal / No
33 / Isolated PNH / Negative / Negative / Striational (1/16) / Normal / No / Not done / Normal / No / Normal / No
34 / Isolated PNH / Negative / Negative / Negative / HyperCKemia (>1000) / No / Normal, No OCB / Normal / No / Normal / Yes
35 / Isolated PNH / Negative / Negative / Negative / HyperCKemia (200-500) / No / Not done / Normal / No / Normal / No
36 / Isolated PNH / Positive nuclear staining / Negative / Anti-PGC (1/640), Anti-SSa, Rheumatoid Factor / Normal / No / Not done / Normal / No / Normal / No
37 / Isolated PNH / Negative / Negative / Anti-Thyroid (weak), ANA (1/160), ANTI-PGC (1/160) / Normal / Mucle biopsy with mitochondrial proliferation and mild myopathic signs. / Not done / Normal / No / Normal / No
38 / Isolated PNH / Negative / Negative / Anti-Smooth Ms (1/80) / Normal / No / Not done / Normal / Yes / Normal / Yes

PNH: Peripheral Nerve Hyperexcitability. VGKC Ab: Voltage-gated Potassium Channel Antibodies. CK: Creatine Kinesa. NCS: Nerve conduction studies. EMG: Electromyography. NMT: Neuromyotonic discharges. ANA: Anti-nuclear antibodies. PGC: Parietal gastric cell. Ms: Muscle ACh: Acetyl-Choline. MGUS: Monoclonal gammopathy of unknown significance. MMN: Multifocal motor neuropathy with conduction block. MRI: Magnetic resonance imaging. OCB: Oligoclonal bands. CMAPs: Compound muscle action potentials. SNAPs: Sensory nerve action potentials. MU: Motor units. PSW: Positive sharp-waves. Fib: Fibrillations