Treatment and Management of Disorders of Neuromuscular Hyperexcitability and Periodic Paralysis

Clinical Presentation

SPS is rare, with an estimated prevalence of one to two cases per million ( ). Classical SPS typically presents with the slow onset of muscle rigidity progressing over the course of months to years. Symptoms usually begin symmetrically in the lumbar and thoracic paraspinal muscles and the proximal lower extremity muscles. The disorder has a female predominance (2–3:1), with onset between 30 and 50 years of age ( ; ). Clinically, episodic muscle spasms are superimposed on muscular rigidity. These spasms, along with difficulty in bending the trunk because of the rigidity, may cause unexplained falls. These falls are often described as “log-like” without the usual reflexive features to soften the impact ( ; ). Voluntary movements become slow and stiff. Gait anxiety is common and ambulation is often cautious to avoid falling. Breathing difficulty may occur due to stiffness in the thoracic muscles and resultant restriction of chest movements. Muscle spasms may be precipitated by movement, auditory or tactile stimuli (startle), or by negative emotion. The spasms are often painful and typically begin with an abrupt jerk followed by a more sustained, tonic contraction that slowly subsides over seconds to minutes. “Status spasticus” or sustained generalized spasms that may last as long as 2 weeks have been described ( ). Stiffness and spasms fluctuate during the day and improve or disappear in sleep. Spasms may be severe enough to cause femoral fractures, joint subluxation or ankylosis, and herniation of abdominal contents ( ; ; ; ). Most descriptions of SPS report sparing of the facial muscles, while some note facial muscle involvement with a “tight-faced” or “pursed-lipped” expression that may limit speech, mask-like facies, risus sardonicus, and dysphagia ( ; ). Abnormalities of eye movements including impaired saccades and gaze evoked nystagmus have been reported ( ; ; ). Rarely, painful spasms provoked by swallowing, resulting in weight loss, may occur ( ). Autonomic dysfunction, with hyperthermia, diaphoresis, pupillary dilation, tachycardia, tachypnea, and hypertension may be seen. Repeated muscle spasms accompanied by autonomic dysfunction necessitating intensive care management have been reported ( ). Rhabdomyolysis may result as a complication of the muscle spasms and rigidity ( ). Sudden death has been noted in about 10% of patients ( ; ).

Focal SPS presents with focal stiffness of a lower extremity, often with progressive involvement of trunk muscles ( ). Myoclonic SPS or “jerking stiff-person syndrome” exhibits the core features of muscle rigidity and spasms with additional characteristics of spontaneous, high-frequency, synchronous myoclonus affecting the axial muscles and lower extremities ( ).

PERM manifests as a more rapidly progressive form of SPS with brainstem dysfunction, dysautonomia, and prominent myoclonus ( ). These patients may require mechanical ventilation and mortality has been described to be as high as 40% ( ). An underlying malignancy may be found in about 20% ( ).

SPS is frequently associated with several autoimmune conditions ( ). Over 30% of patients with SPS have insulin-dependent diabetes mellitus ( ). Studies have also shown an association with autoimmune thyroiditis, pernicious anemia, celiac disease, myasthenia gravis, and, rarely, systemic lupus erythematosus ( ; ; ; ; ; ). SPS may be a paraneoplastic phenomenon in about 5% of patients ( ; ; ). Malignancies associated with paraneoplastic SPS include breast cancer, small cell lung cancer, thymoma, adenocarcinoma of the colon, and Hodgkin lymphoma ( ; ; ; ; ; ). SPS has been described following autologous bone marrow transplant and interferon treatment for multiple myeloma ( ).

On physical examination, patients with SPS exhibit increased tone in the paraspinal muscles. The continuous muscle contractions give rise to a board-like, rigid appearance of the abdomen while co-contraction of the abdominal and paraspinal muscles gives rise to the typical exaggerated lumbar lordosis that is an almost universal finding in individuals with SPS ( Fig. 18.2 ). Muscle hypertrophy may be present, and exaggerated tendon reflexes and loss of abdominal cutaneous reflexes may be seen ( ; ). Although tone may be increased diffusely in the extremities, cog-wheel rigidity and spasticity are absent. The Babinski sign has been described in a few patients ( ). Extrapyramidal, lower motor neuron, sensory, and sphincter abnormalities are absent ( ).

Diagnosis and Evaluation

SPS is a clinical diagnosis supported by autoantibody testing and electrodiagnostic features ( ; ) ( Box 18.2 ). Imaging of the brain and spinal cord is essential to exclude structural mimics of SPS such as focal lesions of the spinal cord (intrinsic cord tumors, syringomyelia, spinal cord ischemia), which have been reported to cause an SPS-like picture ( ; ; ), although SPS itself is not associated with any pathognomonic imaging features. Electrodiagnostic testing is useful in establishing a diagnosis of SPS and differentiating it from other disorders that present with muscle stiffness. Routine motor and sensory nerve conduction studies (NCSs) are normal. On needle electromyography (EMG) of involved muscles, continuous activation of motor unit action potentials (MUAPs) that persists despite attempts at relaxation is observed. The MUAPs appear normal, with a normal firing pattern. The continuous motor activity is abolished by sleep, general anesthesia, peripheral nerve block, and benzodiazepines ( ). There is co-contraction of agonist and antagonist muscles during voluntary movement, instead of the normal pattern of agonist activation and antagonist relaxation ( ). The silent period is normal, in contrast to chronic tetanus, in which the silent period in involved muscles is absent ( ; ). The R1 response of the blink reflex occurs both ipsilaterally and contralaterally, and a third response, R3, occurs bilaterally with stimulus intensity above the detection threshold ( ).

Autoantibodies in SPS ( Fig. 18.3 , Table 18.1 )

Antibodies to GAD were the first to be identified in SPS ( ). Subsequently, other antibodies directed against proteins that are integral to inhibitory neuronal pathways have been described in SPS and SPSD. These proteins include the α1-subunit of the glycine receptor (GlyRα1) ( ; ; ; ), amphiphysin ( ; ; ), gephyrin ( ), dipeptidyl peptidase-like protein-6 (DPPX) ( ; ), and γ-aminobutyric acid-A receptor (GABA-aR) ( ; ) ( Fig. 18.3 , Table 18.1 ).

Table 18.1

Antibodies Associated with Stiff Person Syndrome

	Glutamic Acid Decarboxylase (GAD)	α-1 Subunit of the Glycine Receptor (GlyRα1)	Amphiphysin	GABA-A Receptor–Associated Protein (GABA-aR)	Dipeptidyl Peptidase-Like Protein-6 (DPPX)	Gephyrin
Target	Presynaptic GAD65-synaptic vesicles GAD67-Cytosol	Neuronal cell surface, mediate chloride influx, and hyperpolarization	Presynaptic synaptic vesicle protein	GABA-aR α1 and β3 subunits	Membrane glycoprotein, an auxiliary subunit of Kv4.2 channels (potassium voltage-gated channel subfamily D member 2)	Postsynaptic cytoplasmic protein associated with receptors for GABA and glycine
Frequency	70%	10%	5%			1 case report
Clinical features	Axial muscles in the abdomen and thoracolumbar paraspinals, lower extremity involvement. Variants (stiff limb). May have overlap with cerebellar ataxia and epilepsy.	Prominent myoclonus, cranial nerve, brainstem, autonomic symptoms (PERM phenotype)	Neck and upper extremity involvement	Encephalitis with seizures, opsoclonus-myoclonus, cerebellar dysfunction, limbic encephalitis associated with SPS	Acquired hyperekplexia, cerebellar ataxia, gastrointestinal dysautonomia, psychosis with delusions, hallucinations	Tongue muscle stiffness, dysarthria, and dysphagia
Associated malignancy	Infrequent (∼5%)	10%–20% with malignancy (thymoma, lung, breast, lymphoma)	Breast, lung			Undifferentiated carcinoma of the mediastinum
Other	Frequently associated with other autoimmune disorders (type I diabetes mellitus, thyroid, celiac, pernicious anemia)		Antibody can be associated with sensory neuronopathy, myelopathy	Hashimoto’s thyroiditis, type I diabetes mellitus

GABA, Gamma aminobutyric acid; PERM , progressive encephalomyelitis with rigidity and myoclonus; SPS , stiff-person syndrome.

Anti-GAD antibodies are the most common antibody associated with SPS, present in approximately 60%–80% of patients ( ; ; ). These antibodies are directed against two isoforms of GAD, 65 kDa and 67 kDa ( ; , ). About 80% of SPS patients have serum anti-GAD65 antibodies, while antibodies against the GAD67 isoform occur in less than 50% of patients and at much lower titers ( ; ). While anti-GAD antibodies may also be seen in other disorders such as insulin-dependent diabetes mellitus (IDDM), very high titers are detected in the sera of patients with SPS ( ; ; ; ; ). In IDDM, the antibodies recognize different epitopes of GAD than in SPS. These differences in epitope specificity may explain the low incidence of SPS in patients with IDDM (≈1 in 10,000 persons) ( ; ; ). Serum GAD antibodies may be present in 1% of the normal population and approximately 5% of patients with other neurological disorders ( ). GAD antibodies are usually absent in the cerebrospinal fluid (CSF) of patients with other disorders, while intrathecal synthesis of GAD antibodies is not uncommon in SPS, suggesting that CSF antibodies to GAD are specific for SPS ( ; ). Thus, concurrent testing of serum and CSF has the highest diagnostic accuracy for SPS. Antibodies to GAD are not useful in predicting disease severity, and antibody titers do not correlate with disease duration ( ). CSF oligoclonal bands and elevated IgG index have been described in SPS ( ). GAD antibodies are rarely associated with underlying malignancy in the clinical setting of classical SPS but more frequently so with atypical syndromes ( ).

Initially described in PERM ( ), immunoglobulin G antibodies to GlyRα1 are present in 10%–15% of patients with classical SPS and may also be seen in focal SPS ( ; ; ). Approximately 30% of patients with SPSD are positive for both GlyR and GAD antibodies ( ). GlyRα1 antibodies may be detected in both serum and CSF ( ). Seizures are part of the clinical spectrum in many patients with these antibodies ( ; ). GlyRα1 antibodies may be associated with underlying malignances including breast cancer, lung cancer, thymoma, and Hodgkin lymphoma in up to 20% of patients ( ; ).

Rare patients with SPSD have serum antibodies against amphiphysin, a synaptic vesicle protein ( ; ; ). Compared to anti-GAD–positive SPS, patients with amphiphysin antibodies tend to be older and female. In one study, prominent stiffness of the arms and neck was noted compared to the lower extremity predominant symptoms in SPS associated with anti-GAD antibodies. Diabetes was infrequent in these patients ( ). The presence of anti-amphiphysin antibody defines paraneoplastic SPSD, particularly associated with breast and small cell lung cancer ( ; ; ; ). This association supports prior clinical observations that a paraneoplastic cause should be suspected in SPS involving the upper extremities. Paraneoplastic SPS has also been described associated with anti-Ri (antineuronal nuclear autoantibody type 2, ANNA-2) antibodies ( ; ). Antibodies to gephyrin have been reported in a single patient with SPS and mediastinal cancer ( ).

GABA-aR antibodies may be seen concurrently with GAD antibodies, or as the sole antibody in SPS. The clinical syndrome is variable. In a case series of 12 patients, six had encephalitis with seizures, four had SPS (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Six patients had other neuronal antibodies: GAD65 in five and N-methyl-D-aspartate (NMDA)-receptor antibodies in one. Associated autoimmune disorders included Hashimoto thyroiditis and type 1 diabetes mellitus ( ). Cerebellar dysfunction was noted in 17/25 patients with high GABA-aR antibodies in another series ( ).

Recently, antibodies against DPPX have been described in stiff person spectrum disorders (SPSD). These patients have a clinical picture characterized by acquired hyperekplexia, cerebellar ataxia, and trunk stiffness ( ). Prominent gastrointestinal dysautonomia was a feature in one series; in the same series, 2/20 patients had B-cell neoplasms: gastrointestinal lymphoma and chronic lymphocytic leukemia ( ). Psychosis with delusions and hallucinations may be prominent ( ; ). Approximately 20%–30% of patients meeting diagnostic criteria for SPS lack an identifiable autoantibody.

Treatment and Management

There are two approaches to the treatment of SPS: (1) symptomatic treatment of the rigidity and muscle spasms, usually with agents that potentiate GABA-ergic inhibitory neurotransmission, and (2) immunomodulation ( Table 18.2 ). Agents that have been used for symptomatic therapy include diazepam and other benzodiazepines, baclofen, sodium valproate, levetiracetam, vigabatrin, tiagabine, gabapentin, clonidine, tizanidine, cannabis, and dantrolene ( ; ; ; ; ; ; ; ; ; ; ; ). However, there are few controlled trials of these medications; most data are from case reports or small case series. Vigabatrin is available in the United States only through a special restricted distribution program for approved indications because of the risk of permanent visual loss. Diazepam is usually the first choice unless contraindicated or not tolerated. High doses of diazepam, up to 100 mg/day, may be required ( ). Other benzodiazepines such as clonazepam have also been used ( ). Oral baclofen is usually next in the treatment algorithm and may be used in addition to or instead of benzodiazepines. Intrathecal baclofen may be more effective than oral baclofen, although complications such as spasm-induced rupture and dislocation of the catheter should be borne in mind ( ; ; ; ; ; ). A small double-blind, placebo-controlled trial of intrathecal baclofen in three patients revealed improvement in electrophysiologic parameters in all but clinical improvement was noted in only one ( ). In another more recent retrospective series of seven patients with refractory SPS who underwent intrathecal baclofen, five had improvement in spasticity and pain at 6–12 months. In addition to spinal headache and pump motor malfunction, the most serious complication was Pseudomonas aeruginosa infection at the pump site in one patient ( ). Low doses of continuous intravenous propofol (10 μg/kg/min) were used successfully to control severe spasms as a bridge to intrathecal baclofen in one patient ( ). Botulinum toxin A injections into the paraspinal and limb muscles have improved spasms and rigidity in three case reports ( ; ; ). Tricyclic antidepressants and levodopa may worsen stiffness ( ). Rapid withdrawal of therapy can cause life-threatening worsening of symptoms ( ).

In patients with inadequate response to symptomatic treatment, immunotherapies are the next step. Large controlled clinical trials of any of these treatments are lacking and the evidence is limited to case reports or small case series. Small case series or uncontrolled trials suggest benefit for intravenous immunoglobulin (IVIg) ( ; ). A randomized, placebo-controlled, cross-over trial in 16 GAD antibody–positive SPS patients demonstrated significant improvement in stiffness scores and ability to ambulate and complete household tasks in patients who received IVIg vs. those who received placebo. The duration of benefit ranged from 6 weeks to a year ( ). A recent report of two patients who had good response to IVIg maintained this response up to a year of follow-up when switched to subcutaneous immunoglobulin ( ). Plasmapheresis has both ameliorated clinical symptoms and reduced antibody titers in several case reports of SPS and in isolated case reports of PERM ( ; ; ; ; ). suggested that antibody-negative patients may not respond as well to plasma exchange (PLEX) in a case report of two patients, but reported a good response to PLEX in an antibody-negative patient. A small retrospective case series of nine patients with SPS treated with PLEX noted significant improvement in five patients ( ). The authors performed a literature review and identified 26 patients with SPS treated with PLEX, with improvement in 11 ( ). Prednisone has been reported to improve symptoms in some reports, but not others ( ; ; ; ; ). Single case reports describe a good response and lasting remission of symptoms in SPS with rituximab ( ; ; ; ; ). However, a recent randomized controlled trial (RCT) of 24 patients with GAD antibody–positive SPS failed to show an improvement in the primary outcome, the stiffness index, in rituximab-treated patients over those given placebo at 6 months. The authors noted placebo effect, insensitive outcome measures, and clinical heterogeneity as possible contributors to these negative findings, since four patients reported meaningful clinical improvements that were captured on video recordings ( ). Case reports of treatment with tacrolimus ( ), azathioprine, mycophenolate mofetil, and cyclophosphamide are available ( ). SPS associated with amphiphysin antibodies may be responsive to corticosteroids and treatment of underlying malignancy ( ). Treatment of an underlying malignancy followed by immunotherapy is the usual approach in paraneoplastic SPS ( ). The prognosis is variable and depends on the initial presentation. Persistent symptoms and disability are not uncommon, necessitating ongoing treatments with multiple symptomatic and immune therapies concurrently or sequentially.

Clinical Presentation

Tetanus is preceded by an obvious injury in most patients. In the majority of cases, tetanus arises from minor skin cuts or abrasions that are trivial and not serious enough to seek medical attention ( ). Other risk factors include penetrating injuries, burns, gangrene, ulcers, unsterile intramuscular or subcutaneous injections, septic abortions, and surgical procedures especially with necrotic infections involving bowel flora. In 20%–50% of cases, no obvious portal of entry is seen ( ; ; ). Intravenous drug use is now recognized as a risk factor ( ; ). The average incubation period (time from the presumed infection to the first symptom) is about 3 to 21 days but varies from 1 day to several months depending on the site of the wound, reflecting the distance that the toxin must travel to the nervous system ( ; ; ). The onset time from the first symptom to the first spasm is about 1 to 7 days. Shorter incubation periods and onset times are associated with more severe disease ( ; ).

The disease is characterized by tonic muscle rigidity, intermittent muscle spasms, and dysautonomia. In most patients, the disease is generalized. Early symptoms include irritability, restlessness, tachycardia, and diaphoresis. Trismus or “lockjaw” due to rigidity of the masseters is often the presenting symptom. Spasm of the facial muscles gives rise to the characteristic facies, “risus sardonicus,” or sardonic smile. The rigidity and spasms spread caudally to involve all muscles. Retraction of the head and opisthotonus result from rigidity of the neck and truncal muscles. Superimposed on the rigidity are intermittent spasms, either spontaneous or triggered by external stimuli such as noise, light, or touch. Spasms may be strong enough to cause fractures. Sudden generalized spasms result in opisthotonus, adduction at the shoulders, flexion at the elbows and wrists, and extension of the lower extremities, associated with a rise in body temperature. Consciousness is preserved throughout the illness, and the rigidity and spasms are intensely painful ( ). Respiratory failure may occur due to several factors: chest wall rigidity and spasm, airway obstruction due to pharyngeal and laryngeal spasms, and aspiration pneumonia. The most important direct cause of death is respiratory failure ( ). Autonomic dysfunction may manifest as diaphoresis and cardiovascular instability ( ; ; ). After the first 2 weeks of the illness, once the spasms and respiratory function stabilize, dysautonomia is a major cause of mortality ( ).

Local tetanus is the term used to describe a limited form of the disease characterized by rigidity and spasms restricted to one limb or body region. Local tetanus has a milder course but often progresses to become generalized ( ). Localized tetanus resulting from head injuries and involving the cranial nerves is referred to as cephalic tetanus . It is defined as trismus associated with paralysis of one or more cranial nerves. Cephalic tetanus tends to progress to generalized tetanus in about two thirds of the cases ( ). Tetanus neonatorum , or neonatal tetanus, presents in the first 2 weeks of birth with feeding difficulty and convulsions and is due to poor umbilical stump care in newborns of unimmunized mothers ( ). Lastly, rare cases of “chronic tetanus” that have a prolonged, nonfulminant course over months have been reported ( ; ).

Diagnosis and Evaluation

Tetanus is a clinical diagnosis. Other disorders that may present with muscle rigidity and spasms include tetany, SPS, dystonic reactions, strychnine poisoning, and rabies. Wound cultures often do not detect C. tetani or may detect the organism in patients without tetanus ( ). Tetanus is rare, but not unknown, in the presence of protective concentrations of antibody (serum antibody titers >0.1 IU/mL by enzyme-linked immunosorbent assay) ( ; ). Bioassays can detect tetanus toxin in the serum and may be useful when there is clinical suspicion of the disease in patients with low antibody titers. However, a negative bioassay does not exclude tetanus ( ). Electrophysiologic studies in patients with chronic tetanus reveal an increase in the F-response amplitude to M-response amplitude ratio (F/M ratio). The silent period is usually absent but may be normal ( ; ; ; ). Motor units are usually normal; the spasms are characterized by involuntary bursts of motor unit activity ( ).

Treatment and Management

Three principles guide the management of tetanus: (1) control of active C. tetani infection to stop further production of toxin, (2) neutralization of circulating toxin, and (3) supportive care. Wound debridement is essential to eliminate the anaerobic environment that encourages the growth of C. tetani . Penicillin G was the traditional antibiotic of choice, in a dose of 100,000 to 200,000 IU/kg/day in divided doses intravenously for 7 to 10 days. However, the GABA-antagonistic properties and epileptogenic effects of intravenous penicillin have raised concerns about the use of penicillin in tetanus ( ). Therefore, metronidazole is often used preferentially as the first-line antibiotic, 400 mg rectally or 500 mg intravenously every 6 hours for 7 to 10 days. An open, nonrandomized study reported 24% mortality (18/76 patients) in patients receiving procaine penicillin, compared with 7% (7/97 patients) in those receiving metronidazole ( ). In a large study by , although mortality rate was no different in patients treated with metronidazole or penicillin, patients treated with metronidazole required fewer muscle relaxants and sedatives. An unblinded randomized trial demonstrated similar requirement for tracheostomy and mechanical ventilation, requirement for neuromuscular blockade, and frequency of dysautonomia, nosocomial infections, and mortality in patients treated with intramuscular benzathine penicillin, intravenous benzyl penicillin, or metronidazole ( ). Alternative antibiotics include erythromycin, tetracycline, chloramphenicol, and clindamycin ( ; ).

Tetanus toxin that is bound to the central nervous system cannot be neutralized. However, neutralization of circulating toxin with human tetanus immune globulin (HTIG) improves survival and is considered standard of care. HTIG is usually given in a dose of 3000 to 6000 units intramuscularly ( ). In the UK, intravenous HTIG is used ( ). In a large case series from India, no antitoxin and low dose of antitoxin were associated with higher mortality ( ). A Brazilian randomized controlled study compared intrathecal tetanus immunoglobulin plus intramuscular immunoglobulin to intramuscular immunoglobulin alone in 128 patients with tetanus. Patients treated with both intrathecal and intramuscular immunoglobulin had a shorter duration of spasms and hospitalization and a reduced need for assisted ventilation. It is not clear, however, whether tetanus immune globulin or human lyophilized immunoglobulin was used ( ). However, the conclusions of two meta-analyses are inconsistent regarding the benefit on intrathecal immunoglobulin ( ; ). Two open studies published subsequent to the meta-analyses reported lower mortality with intrathecal immunoglobulin ( ).

Supportive care of tetanus includes the treatment of muscle rigidity and spasms and treatment of dysautonomia. Several agents have been used, but controlled trials are few. Benzodiazepines serve the dual purpose of controlling spasms and rigidity and reducing autonomic instability. Diazepam is most commonly utilized, and large doses may be required, 3 to 8 mg/kg/day. A Cochrane review that included two trials concluded that diazepam may be more effective at reducing mortality than chlorpromazine or phenobarbital ( ). The large doses required, combined with the long half-life (72 hours) and the presence of active metabolites, commonly result in respiratory depression necessitating ventilatory support ( ). Midazolam, 5 to 15 mg/hour, and propofol, 20 to 80 mg/hour, intravenously have also been used with some success in case reports and small case series ( ; ; ). Other agents used for sedation include phenobarbital, morphine, and chlorpromazine ( ; ; ). Intravenous ketamine (2 mg/kg) alternating with diazepam has been used in one case report of cephalic tetanus with severe laryngospasm ( ). Oral baclofen does not penetrate the blood-brain barrier. While intrathecal baclofen has been reported to be useful for muscle spasms in case reports and case series, three case series found higher rates of mortality than that reported for other agents and a high incidence of adverse effects including respiratory depression and meningitis ( ; ; ; ; ; ). Studies of magnesium sulfate have provided conflicting results for the control of spasms and management of dysautonomia ( ; ; ; ; ). A meta-analysis of three RCTs did not show benefit of magnesium sulfate compared to diazepam on mortality. Other outcomes including hospital stay and need for mechanical ventilation were conflicting ( ; ; ; ).

Neuromuscular blockade is used when sedation is inadequate to control the spasms. Pancuronium has been used, but may worsen autonomic dysfunction due to catecholamine reuptake inhibition ( ). Vecuronium has the advantage of minimal cardiovascular side effects but is short acting and requires continuous infusion ( ). Dantrolene was reported to be useful in controlling spasms without need for neuromuscular blockade in one case ( ).

Although sedation is the first line in the management of dysautonomia, several other classes of agents have been used to control hypertension and tachycardia. Morphine may be useful in the management of dysautonomia because it does not worsen cardiovascular instability ( ; ). Beta blockade with propranolol does not appear to be beneficial; on the contrary, it may cause hypotension, pulmonary edema, and even sudden death ( ; ). Labetalol is also not recommended for similar reasons ( ). Esmolol infusion was used with success in a single case report ( ). Small series and case reports of the use of clonidine, atropine, and epidural or spinal bupivacaine are available ( ; ; ; ).

Ancillary care includes early tracheostomy and ventilatory support, management of tracheal secretions, nutritional support including gastrostomy tube placement, prophylaxis of deep venous thrombosis, management of nosocomial infections, and prevention of decubiti and gastrointestinal stress ulcerations. Corticosteroids were found to reduce mortality in an open labeled study of 63 patients with severe tetanus ( ). Administration of tetanus toxoid in three doses at least 2 weeks apart after recovery is recommended because the disease does not confer immunity.

Isaacs Syndrome

Isaacs syndrome , or acquired autoimmune neuromyotonia, is characterized by continuous muscle fiber hyperactivity that manifests with muscle stiffness, fasciculations, and clinical myokymia and is characterized clinically by continuous vermiform movements across muscles that have been likened to a bag of worms under the skin ( Table 18.3 ). The disorder is usually insidious in onset, with a male predominance (M:F 2:1) and average age of onset in the mid-40s ( ), although it has been reported in infants and children ( ; ). The movements are usually seen in distal and proximal limb muscles but may also involve the axial muscles, face, and tongue ( ; ). Dyphonia and dyspnea due to involvement of laryngeal muscles have been reported ( ). Persistent contraction of muscles results in abnormal postures with flexion or extension of the hands and feet, resembling carpopedal spasm. Other features include muscle cramps that may worsen following voluntary muscle contraction. Hyperhidrosis and muscle hypertrophy are frequently present and are attributed to the continuous muscle fiber activity. Pseudomyotonia is a clinical diagnostic feature of Isaacs syndrome but is seen only in about a third of the patients. It refers to delayed muscle relaxation after voluntary contraction without percussion myotonia and is so termed to differentiate it from myotonia, which originates in the muscle membrane. It commonly affects hand grip. Weakness is reported in approximately a third of patients, usually involving the most overactive muscles. Pain and paresthesia are not uncommon. Tendon reflexes may be normal or absent ( ; ; ; ; ). The continuous muscle activity persists during sleep and general anesthesia. The response to peripheral nerve block is variable but it is abolished by neuromuscular blockade with curare, establishing the distal peripheral nerve as the impulse generator ( ). A report of hypersensitivity to a nondepolarizing muscle relaxant (rocuronium), causing prolonged postoperative paralysis highlights the need for caution during surgical procedures ( ).