Peripheral Nerve Hyperexcitability Syndromes (PNH)
Peripheral nerve hyperexcitability syndromes are a group of disorders characterized by muscle stiffness, cramps, and muscle twitches with involuntary abnormal electrical activity on needle EMG. Peripheral nerve hyperexcitability syndromes are distinct from the disorders of muscle stiffness originating in the central nervous system (CNS), such as spasticity and stiff person syndrome, and from muscle disorders such as the myotonias, rippling muscle disease, and glycogen storage diseases.
3 main types:
Cramp-fasciculation syndrome,
Isaacs syndrome
Morvan syndrome
Patients with cramp-fasciculation syndrome present with myalgia and cramps without weakness. Examination may show fasciculations, myokymia, or both in muscles with an otherwise normal neuromuscular examination. The condition is considered a benign syndrome, and the pathophysiology involves instability of the distal motor axon. The workup includes electrodiagnostic studies. Needle examination demonstrates fasciculation potentials and normal motor unit action potential morphology and recruitment. Supramaximal stimulation of motor nerves at 0.5 Hz, 1 Hz, 3 Hz, and 5 Hz may show after discharges following the initial motor response. Voltage-gated potassium channel (VGKC) complex antibodies may be seen in some patients with cramp-fasciculation syndrome, suggesting an autoimmune parthenogenesis, as is the case with other peripheral nerve hyperexcitability syndromes. The presence of antibodies against voltage-gated potassium channels which suppress the outward potassium current and consequently affect neuronal excitability.
Patients with cramp-fasciculation syndrome respond to treatment with carbamazepine 200 mg to 400 mg 2 times a day.
A clinical syndrome in which generalized myokymia is a prominent component. The spontaneous motor activity originates from the distal segments of peripheral nerves, since it was not eliminated by blockade of the peripheral nerve but could be eliminated by curare. VGKC complex autoantibodies were identified in many patients with Isaacs syndrome. In some, the disorder is considered paraneoplastic since it is associated with a neoplasm, mainly thymoma and small cell lung cancer, usually associated with VGKC complex autoantibodies. It may affect patients at any age and varies significantly in severity. In most cases, it manifests with generalized muscle stiffness (neuromyotonia) and slowness of movement. The stiffness persists during sleep. Clinical manifestations include muscle hypertrophy (mainly calf muscles), continuous muscle twitching, and undulation (myokymia). Trousseau and Chvostek signs may also be present. Dysarthria and dysphagia may occur when abnormal muscle activity affects bulbar muscles. In severe cases, muscles and posture may be rigid. Signs of dysautonomia, including hyperhidrosis, sialorrhea, piloerection (goose flesh), and abdominal pain, are frequent. Sensory manifestations are rare but may include paresthesia and neuropathic pain. The clinical symptoms of Isaacs syndrome may fluctuate but are usually slowly progressive over years.
Needle EMG examination reveals a variety of spontaneous motor unit activities that include fasciculation potentials, myokymic discharges, and neuromyotonic discharges. These originate from one or more segments of the peripheral motor axon and are not blocked by general anesthesia but are eliminated by neuromuscular junction blockade. The presence of VGKC complex antibodies in both Isaac and Morvan's syndrome indicates a common underlying pathophysiology. Both neuromyotonic and myokymic discharges may be detected in patients with Isaacs and Morvan. Most patients with Isaacs syndrome have evidence of autoimmunity and respond to immunomodulation. Anti-VGKC antibodies are, in fact, mainly directed at proteins surrounding the potassium channel rather than the channel itself; thus, they are now known as VGKC complex antibodies. These cell-surface autoantibodies are directed against leucine-rich glioma inactivated protein 1 (LGI1) and contactin associated protein like 2 (CASPR2). The presence of CASPR2 antibodies in the CSF is more specific for limbic encephalitis than Isaacs or Morvan syndromes.
The co-discovery of other antibodies in Isaacs syndrome, including those targeting collapsing response-mediator protein-5 (CRMP5) cardiolipin, glutamic acid decarboxylase (GAD), netrin-1, MuSK, and immunoglobulin-like cell adhesion molecule5 (IgLON5), adds to the complexity. The pathophysiological relevance of these is yet to be determined.
Pathologic findings in patients with Isaacs syndrome are not prominent. Muscle biopsy is usually normal. Sensory nerve biopsies may show thickening of myelin sheaths and splitting of the inner myelin lamellae, widening of the cytoplasm of Schwann cells by tubulovesicular inclusions and lysosomes, and lysosomal abnormalities in cultured sural nerve Schwann cells.
Associations: Other autoimmune conditions, particularly myasthenia gravis, but also dermatomyositis, Sjögren’s syndrome and systemic lupus erythematosus. The identification of a PNH syndrome can herald a range of benign and malignant neoplasms, mainly thymoma (often with coexistence of anti-acetylcholine receptor antibodies) and small cell carcinoma of the lung. ALS, CIDP, amyloid-light chain amyloidosis, hyporparathyroidism, hematological malignancies.
It has also been described after certain pharmacological treatments, including anti-tumournecrosis factor therapy, penicillamine, oxaliplatin, pancreatic cancer treatment and the human papillomavirus vaccine and after severe wasp sting.
Symptomatic treatment includes phenytoin or carbamazepine, which are often effective in reducing muscle stiffness, twitching, and cramps. In Isaac's syndrome, carbamazepine 200 - 400 mg 2 times a day. Phenytoin, sodium valproate, lamotrigine, acetazolamide are others. For Patients with confirmed autoimmune origin, plasma exchange, corticosteroids, or IV immunoglobulin (IVIg) treatment can be used, particularly in patients who remain symptomatic. Patients may require combination therapy. Reports have described the use of other medications, including cyclophosphamide, azathioprine, cyclosporine, and rituximab.
Caution is advised during anaesthesia, particularly with the use of non-depolarising muscle relaxants (e.g.rocuronium), which may require smaller doses than usual.
A 41-year-old woman noticed increasing leg stiffness and difficulty with gait. The symptoms started 2 to 3 years before her presentation for a neurologic consultation. She was aware of muscle twitches in her limbs and increasing leg muscle spasms and cramps. She was in very good health otherwise and was not aware of any sensory symptoms, cognitive changes, or sphincter disturbance. On neurologic examination, mental status and cranial nerves were normal. Muscle bulk was normal. She had frequent muscle twitches in her limb muscles and poor relaxation of muscles in the arms and legs with no clear spasticity or rigidity. Her sensory examination was normal. Deep tendon reflexes were 2+ throughout, and her gait was slightly stiff and antalgic. Romberg test was normal. Electrodiagnostic testing revealed normal sensory and motor nerve conduction studies. Needle EMG revealed myokymic discharges with neuromyotonic discharges in several muscles in the upper and lower extremities. Muscle cramps were also recorded. Laboratory studies revealed normal creatine kinase and inflammatory markers. Serum voltage-gated potassium channel complex antibodies were significantly elevated (titer greater than 0.8 nM, negative value less than 0.2 nM). Glutamic acid decarboxylase (GAD) and amphiphysin antibodies were negative. CT of her chest, abdomen, and pelvis was unrevealing.
She was diagnosed with Isaacs syndrome and treated with carbamazepine 200 mg 2 times a day, with improvement of stiffness within several weeks. Carbamazepine was increased to 400 mg 2 times a day, with almost total resolution of symptoms.
Comment. This case illustrates several characteristic features of Isaacs syndrome. First, presenting symptoms of muscle twitches, cramps, and spasms are nonspecific. Neurologic examination is largely normal except for muscle twitches. Needle EMG is especially helpful to localize the pathology to the motor axon, showing myokymic and neuromyotonic discharges. EMG also excludes myotonia, which is seen in certain myopathic conditions. Voltage-gated potassium channel complex antibodies are often elevated in Isaacs syndrome.
Morvan syndrome is a disorder with features of peripheral nerve hyperexcitability, dysautonomia, and encephalopathy. The diagnosis of Morvan syndrome puts emphasis on the presence of central and autonomic disturbances, in addition to peripheral hyperactivity.
It is also associated with VGKC complex antibodies and neoplasms, especially thymoma. Morvan syndrome affects males more than females, with symptoms of peripheral nerve hyperexcitability that are often the presenting features. Neuropathic pain in the limbs may be a feature. In a small case series of patients with Morvan syndrome and neuropathic pain, nerve conduction studies were normal. It is postulated that the autoimmune condition affects different parts of the neuraxis, including small fiber nerves. Hyperhidrosis is a common dysautonomic symptom. Other signs of autonomic dysfunction reported in patients with Morvan syndrome include tachycardia, arrhythmia, and urinary dysfunction. CNS features include hallucinations, agitation, delirium, amnesia, and confusion. Sleep disturbances are common, especially insomnia. MRI has been found to be normal in the majority of patients with Morvan syndrome. Thymoma was present in more than one-third of patients in a report of 29 patients, some of whom also had a diagnosis of myasthenia gravis with positive acetylcholine receptor antibodies. VGKC complex antibody levels are elevated in a majority of patients with Morvan syndrome, and as with Isaacs syndrome, they are actually directed against associated channel proteins. Patients with Morvan syndrome have elevated antibodies to CASPR2, LGI1, or both. Patients who are CASPR2 antibody positive have thymoma more often than patients who are LGI1 positive. Patients with Morvan syndrome without antibodies to currently known VGKC complex proteins have been reported, suggesting more antigens are yet to be discovered. Morvan syndrome shares features with limbic encephalitis, a CNS disorder. Several characteristics differentiate the two, one of which is that CASPR2 antibodies are more commonly associated with Morvan syndrome than are LGI1 antibodies. Morvan syndrome is distinguished by peripheral nerve hyperexcitability by neuropathic pain, and dysautonomia.
Morvan syndrome is distinguished from Isaac syndrome by the presence of central features: Encephalopathy, insomnia, vivid complex hallucinations, delirium, and spatial and temporal disorientation. Other features: Hyponatremia and autonomic involvement can result in hyperhidrosis, fever, sialorrhoea, constipation, arrhythmias, hypertension, and weight loss.
MRI abnormalities in limbic encephalitis include unilateral or bilateral medial temporal hyperintensities. Abnormal MRI findings were rarely seen in a case review of patients with Morvan syndrome. As in Isaacs syndrome, needle EMG in patients with Morvan syndrome shows evidence of motor unit hyperexcitability in the form of fasciculations, multiplets, myokymic discharges, or neuromyotonia. In addition to obtaining an EMG study for patients suspected of having Morvan syndrome, a search for malignancy at the time of diagnosis is recommended. Other testing includes brain MRI, EEG, and polysomnography. Laboratory workup should include evaluation for VGKC complex antibodies to CASPR2 and LGI1, as well as acetylcholine receptor antibodies when concurrence of myasthenia gravis is suspected.
Treatment: Symptomatic treatment included carbamazepine, phenytoin, sodium valproate, and levetiracetam, while some respond to immunotherapy (steroids, intravenous immunoglobulin, or plasma exchange).
The classic syndromes associated with high-level VGKC complex antibodies include Isaacs syndrome, Morvan syndrome, limbic encephalitis, and possibly cramp-fasciculation syndrome. High-level VGKC complex antibodies have also been seen occasionally in patients with other possible autoimmune disorders, such as cerebellar syndrome, intractable epilepsy, and pain syndromes. Low-level VGKC complex antibodies are less specific and present in a variety of nonautoimmune disorders.
Most patients with peripheral nerve hyperexcitability syndromes have CASPR2 autoimmunity, while patients with limbic encephalitis have LGI1 autoimmunity. However, this is not exclusive and significant overlap exists, with neuropathic pain, cerebellar symptoms, cognitive symptoms, and epilepsy frequently occurring in a significant number of patients with CASPR2 autoimmunity and peripheral nerve hyperexcitability syndromes occurring in some patients with LGI1 autoimmunity.
Episodic ataxia type 1 (EA1) is characterized by frequent spells of gait imbalance and upper limb incoordination, typically lasting about 15 minutes, as well as interictal myokymia of skeletal muscles. EMG may be needed to reveal subclinical myokymia. During an attack, a range of other symptoms may be present, including vertigo, blurred vision, diplopia, dysarthria, weakness, tremors, and diaphoresis. Attacks can be triggered by emotional stress, startle or exertion, and onset is typical during childhood or early adolescence with reports of some attacks abating in adulthood. The frequency of ataxic episodes can be improved by phenytoin or acetazolamide. Excitability testing in EA1 showed increased superexcitability and threshold electrotonus changes.
Episodic ataxia type 2 (due to CACNA1A mutations) does not cause myokymia,
Mutations in KCNA1 or KCNQ2 can lead to familial neuromyotonia, while KCNQ2 mutations are also reported to cause benign familial neonatal convulsions and myokymia. Clinical overlap between neuromyotonia and a motor-predominant, axonal Charcot-Marie-Tooth neuropathy exists as a result of recessive mutations in histidine triad nucleotide-binding protein1 (HINT1).
Myotonia congenita (caused by CLCN1 chloride channel mutations; mode of inheritance either dominant[Thomsen disease] or recessive [Becker disease]) and paramyotonia congenita (caused by SCN4A sodium channel mutations) are briefly mentioned to highlight their distinctly myopathic nature, warranting diagnostic consideration in patients with delayed relaxation of muscles and an appropriate family history.
Rippling muscle disease is a benign myopathy with symptoms and signs of muscular hyperexcitability. The typical finding is a rolling wavelike mounding of muscle provoked by mechanical stimuli and stretch, which is electrically silent during EMG recording. Rippling muscle disease is associated with mutations in the gene encoding caveolin 3 (CAV3), a membrane associated protein localized to skeletal muscle fibers. The disorder has immune associations, including acetylcholine receptor antibody positive myasthenia gravis and thymoma.
The nondystrophic myotonias, and specifically myotonia congenita, often present with muscle stiffness that manifests when attempting to initiate movement after a period of rest and diminishes with repeated activity and muscle contractions. Needle EMG in these patients shows prominent myotonic discharges without myopathic motor unit action potential changes.
The myotonic dystrophies, including myotonic dystrophy type 1 and type 2, present to clinical attention with muscle weakness but may have stiffness and muscle pain that is distinct from, but related to, myotonia. These disorders have frequent nonmuscular manifestations that help establish the diagnosis, including cataracts, cardiac conduction defects, and characteristic facies. Needle EMG shows characteristic myotonic discharges rather than myokymic or neuromyotonic discharges.
Schwartz-Jampel syndrome, or chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by the triad of myotonia, facial dysmorphism, and skeletal deformities. Common features include clinical myotonia, muscle stiffness, hypertrophy, and contractures. Facial dysmorphisms include puckered small mouth, blepharophimosis, and blepharospasm; skeletal abnormalities include short stature, kyphosis, hip dysplasia, and pseudofractures. Muscle enzymes are normal or slightly elevated. Nerve conduction studies are normal. Needle EMG reveals continuous myotonic discharges at rest. The disorder results from mutations in the HSPG2 gene in chromosome 1p34-36.1, which encodes perlecan, a major component of basement membranes.
Inherited d/o
EA type 1 with myokymia (Kv1.1; KCNA1)
Benign familial neonatal epilepsy and myokymia (KCNQ2)
Autoimmune d/o
Cramp-fasciculation syndrome
Acquired neuromyotonia (Isaacs syndrome)
Not infrequently, this is associated with neoplasm, especially thymoma, and the specific channels affected are the dendrotoxin-sensitive fast potassium channels.
Morvan syndrome
Paraneoplastic neuromyotonia
Thymoma (with or without MG)
Small cell lung carcinoma
Nerve injury
Radiation toxicity
Inherited neuropathies (CMT-2)
MS (facial myokymia)
Neuropathies with conduction block
Focal compressive neuropathy
Chronic motor nerve disorders (ALS)
Amyloidosis
Uremia
Intraoperative nerve irritation (called neurotonic discharges)
Toxins
Timber rattle snake venom
Black widow spider venom (alpha-latrotoxin)
Green mamba venom (alpha-dendrotoxin)
Pyridostigmine
Oxaliplatin
Gold
Disorders mimicking PNH
Muscle disorders: myopathies with myotonia, myotonic dystrophy type 1 and 2, non-dystrophic myotonia, HyperKPP, toxic myopathies, contracture (electrically silent), metabolic myopathies, rippling muscle disease (electrically silent) - AD type 1 and type 2.
CNS disorders: Stiff Person syndrome, tetanus, spasticity.
Focal Myokymia (Face)
Multiple sclerosis
Brainstem mass lesion (eg, glioma)/Pontine tumor
Cerebellopontine angle mass lesion/Vestibular schwannoma
Basilar invagination
Syringobulbia
Obstructive hydrocephalus
Guillain-Barre´ syndrome
Bell’s palsy
Neurosarcoidosis
Neurocysticercosis
TB meningitis
ALS
SCA type II and III
Kufor-Rakeb syndrome/PARK9
MSA
Familial dyskinesia and facial myokymia
Iatrogenic head and neck radiotherapy
Focal Myokymia (Limb)
Radiation plexopathy
Carpal tunnel syndrome
Ulnar mononeuropathy
Peripheral nerve injury
Radiculopathy
Generalized Myokymia
Isaacs syndrome
Morvan syndrome
Guillain-Barre´ syndrome
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Charcot-Marie-Tooth disease
Amyotrophic lateral sclerosis
Thyrotoxicosis
Heavy metal exposure (eg, gold, platinum compounds, lithium, mercury, or manganese)
Penicillamine therapy
Timber rattlesnake envenomation
On a Synergy-Natus machine, the cramp-fasciculation protocol is under the "RNS" (repetitive nerve stimulation) Folder.
Open the RNS folder. It will prompt you to select a protocol to use.
Select "Generic Muscle Cramp Fascic" Protocol, and the appropriate side. Then click "OK."
You will need to change the muscle label.
Right click on "Generic muscle" Blue type on top right window.
The protocol name should change in the lower left of the pop up window, to the correct muscle.
When correction has been made select "OK."
You will need to change the sweep speed to 50 ms to acquire a baseline.
In the top left waveform window, change the sweep from "10s" to 50 ms using the left and right arrows.
The gain is 5 mV
Now you can acquire the baseline CMAP as you would for any motor nerve.
Once you have acquired a supramaximal response, click the "next" button on the controller pad.
The "Baseline" row in the table will change color to blue and you will need to stimulate once more to record an official entry.
Click the "Next" button to advance the table row.
You will now have to change the sweep back to "10s" using the instructions provided previously.
Change the sensitivity to 200 uV.
Patient must not tense up during the stimulation. They must stay relaxed in order to obtain an accurate analysis.
The frequency will change automatically as you advance (click next) during the study.
Notice, you will be on "2 Hz" run in the table. This is indicated by the color Blue in the table.
When the above has been verified, and the patient has been instructed. You are ready to deliver a train of stimulation.
When you are ready press the "single" stimulation button on the controller pad. A series of 4 stimuli at the indicated frequency will be delivered.
You can now press "next" on the controller pad to advance to the next row.
Notice the "Hz" indicator has changed to the new frequency.
Wait at least 10 seconds before delivering the next train.
When the patient is ready and you have verified setting, you can continue with the protocol.
This stimulation acquisition pattern repeats until all frequencies have been delivered.
Assess the tibial nerve - AH first on one side. If study is negative, test the contralateral side. If that study is negative as well, .check ulnar to ADM.
A positive response is when cramp discharge last >3 s.
By localization:
Neuronopathies: ALS
Neuropathies: CMT, GBS, CIDP, Isaac syndrome
DNMT: MG
By etiology:
Radiation: Brain, head and neck
Neoplasia: SCLC, thymoma, Hodgkin diseae
Drugs: Penicillamine
Immune mediated: Primary systemic sclerosis, BMt
Familial: Autosomal dominant neuromyotonia
Amyloidosis
HINT1-associatedCharcot-Marie-Tooth neuropathy