Gary Oh

Lori is a 49 yo married female. 10 months prior to admission she began experiencing progressive muscular weakness mostly in the lower limb. The illness waxed and waned, with bouts of improvement and aggravation. This progressive muscular weakness resulted in walking impairment.

She also described intense muscular pain, a loss of 10 kg in 10 months, xerostomia, and reduction of the libido.

??What are the signs and symptoms???

Lori is a 49 yo married female. 10 months prior to admission she began experiencing progressive muscular weakness mostly in the lower limb. The illness waxed and waned, with bouts of improvement and aggravation. This progressive muscular weakness resulted in walking impairment.

She also described intense muscular pain, a loss of 10 kg in 10 months, xerostomia, and reduction of the libido.

??What is the dDx???

DIFFERENTIAL DIAGNOSIS

??What further testing do you need???

Neuro exam normal, CN normal, Muscle tone/bulk normal. Strength 4/5

DTR: 1+ (rest) and 2+ (physical effort) Sensory normal Normal CBC+diff, ESR, lytes, Ca, Mg, urea, Cr, gluc, bili, ALT, alk

phos, LDH, CK, ANA, TSH, T3 and T4 Electrophysiologic study

Amplitude reduction of compound muscular action potentials (CMAP) on right ulnar and fibular nerves.

Sensory and nerve conduction velocities normal. Needle EMG was normal. Thorax X-rays and CT scan were normal. Ab echo normal, Pelvic echo normal. Mammography was normal and Pap negative. Muscle Bx - Type II fiber atrophy suggesting early denervation. Autoantibodies tests

-Positive Calcium channel binding antibodies type-N and type P/Q -Negative Acetylcholine receptor binding antibodies

??What is the diagnosis???

Lambert-Eaton Myasthenic Syndrome (LEMS)

Incidence

Uncommon, true incidence unknown Occurs much less frequently than myasthenia gravis Middle-aged adults 50% of LEMS associated with a malignancy (small cell

lung cancer (SCLC)) 3% of SCLC have LEMS Other tumors are lymphoproliferative disorders

(Hodgkin lymphoma), "atypical" carcinoid and malignant thymoma

27% have other autoimmune disorders (DM Type 1 or Thyroid)

+FHx - Families of pts with non-paraneoplastic LEMS have an increased frequency of autoimmune diseases, while families of patients with paraneoplastic LEMS do not.

Symptoms Similar to MG Slowly progressive proximal muscle weakness

Gait alteration , difficulty arising from a chair or managing stairs. Aching or stiff muscles, muscle fatigability or cramping (after

protracted exercise) Symmetrical preservation of distal lower muscle function. Modest upper

extremity complaints. LEMS is unlikely in patients with limb weakness confined to the arms

Autonomic dysfunction (Dry mouth , ED, blurred vision and constipation) CN involvement possible (less severe than in MG), ptosis, oropharyngeal

symptoms (dysarthria, dysphagia, and difficulty chewing) Respiratory failure. Thus, LEMS must be considered in the differential

diagnosis of patients presenting with neuromuscular respiratory failure. Both paraneoplastic and autoimmune form of LEMS have similar Sx/Sx.

With cancer, age of onset is later and possibly more rapid progression of neurologic symptoms

Signs Deep Tendon Reflexes (DTRs )are almost always depressed or

absent. Postsynaptic /postexercise facilitation

10sec Maximal isometric contraction may lead to temporary reappearance of previously depressed or absent DTRs/temporary improvement of muscle weakness.

This defining bedside clinical observation and should be part of the routine examination of a patient with proximal muscle weakness or even complaints of weakness, especially when hyporeflexia or areflexia are conjoined.

Thus with facilitation, reflexes and muscle power testing are best performed after a period of rest.

dDx MG: Another useful clinical sign is excessive or paradoxical eyelid elevation may occur after sustained upgaze in patients with LEMS . This finding is in opposite to fatigable ptosis common in MG during the same maneuver.

Interestingly, LEMS has a pattern more suggestive of a myopathy than an NMJ disorder, with slowly progressive proximal lower extremity weakness, distinctive autonomic findings, a smattering of oculobulbar findings, and recovery of lost deep tendon reflexes or improvement in muscle strength with vigorous, brief muscle activation.

Pathophysiology

Antibodies directed against the voltage-gated calcium channel (VGCC) interfering with the normal pre-synaptic calcium influx required for Ach release

Among these, the L-type, N-type, and P/Q-type VGCC are the most important.

P/Q-type VGCCs make up more than 95 percent of the functioning receptors at the neuromuscular junction (NMJ) and probably represent the main immunologic target in LEMS

The expression of functional VGCCs in the surface membrane of small cell lung cancer (SCLC) cells is probably responsible for most if not all cases of paraneoplastic LEMS

???What is the recommended testing??

Clinical + VGCC antibodies + nerve conduction studies. An aggressive search for a primary underlying malignancy is central

to the management of patients with LEMS. Radioimmunoassay

Antibodies against P/Q-type VGCC (85 to 95%) Antibodies against N-type VGCC (30 to 40 %)

Low frequency of VGCC antibodies in healthy controls, MG pts, and other autoimmune diseases (high specificity)

Antibody test alone is not diagnostic, neurophysiology required Electrophysiologist

The pattern in LEMS is distinctly different from the postsynaptic NMJ changes seen in MG.

Isolated reduced baseline amplitude compound muscle action potential (CMAP) Postactivation facilitation

Increase in the CMAP amplitude following high frequency stimulation Following high frequency (10 to 50 Hz) repetitive nerve stimulation (RNS)

(waveform 1 ) or brief (eg, 10 seconds) maximal isometric muscle activation (waveform 2), there is a significant increment with a marked increase in the CMAP amplitude.

Postexercise facilitation - the increase in CMAP amplitude after brief isometric exercise.

Electromyography (EMG) - motor unit action potentials are often unstable

Single fiber EMG (SFEMG) - significant jitter and transmission blocking that is characteristically improved at higher firing rates

LEMS usually have significant nerve conduction study abnormalities with relatively well-preserved strength, while patients with MG usually have modest EMG abnormalities in the face of rather significant weakness and fatigability

???What is the recommended treatment??

Treatment

Aggressive search for a primary underlying malignancy (SCLC) is central

Guanidine - inhibits voltage-gated K channels and enhances the release of ACh. Significant toxicity limits use. SE include bone marrow suppression and renal toxicity.

Aminopyridines (Dalfampridine) - significant prolongation of the nerve terminal membrane depolarization enhancing Ca entry and improving Ach release.

AChEI (Pyridostigmine) - Reduce the metabolism of ACh. Intravenous immune globulin (IVIG) - Useful with MG and

LEMS reducing the mass of voltage-gated Ca channel antibodies

Immunosuppressive agents - Prednisone alone or combined with Azathioprine or Plasmapheresis

Plasma exchange (Plasmapheresis) Patients with LEMS do not respond as rapidly

to plasma exchange as do those with MG. In addition, the benefit of plasma exchange is only short term, due to continued production of the offending antibodies, and repeated treatment is necessary. Nevertheless, combined therapy with plasma exchange and oral immunosuppressive agents remains a beneficial approach for some patients.

??What is the prognosis??

Prognosis Difficult to assess Determined by the presence/type of any underlying cancer, the

presence/severity associated autoimmune disease, and the severity/distribution of weakness.

Patients with rapidly progressive symptoms usually have more severe disease.

Thus maintain quality of life LEMS does not seem to affect the respiratory system as significantly

as MG does. In most patients, weakness does not severely affect vital muscles. Maximum severity usually becomes established within several months of symptom onset.

Meds provide partial symptom relief, but usually progression over time.

Without treatment, weakness and dysfunction do not usually vary. Exceptions are during periods of exacerbation induced by intercurrent illness or by medications that impair neuromuscular transmission.

Death often results from the underlying malignancy.

LEMS frequently heralds cancer. This association is important in overall

morbidity, since there is a very short survival time with SCLC.

Because LEMS may lead to early detection of SCLC, prognosis of SCLC in patients with SCLC-LEMS is better than in SCLC without LEMS.

When LEMS has been symptomatic for at least 2 years and no underlying cancer has been demonstrated, the LEMS was probably caused by an autoimmune process. At that point, prognosis is determined by severity of dysfunction and the presence and severity of other autoimmune conditions.

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