Case Vignettes in Neurology

PATIENT CASE STUDIES

Case 12 2/23/99 Myopathy
Case discussion This 18-year old female was evaluated for ophthalmoplegia and progressive muscle weakness. At the age of 6 years she was noted to have a squint and was given glasses. At seven she complained of double vision that gradually resolved. She did reasonably well until her early teens when she found herself unable to compete with other children at play. Approximately one year prior double vision recurred. For the past 6 months she complained of progressive generalized weakness and has difficulty rising from a seated to standing position. On examination she was of short stature with ptosis and a paucity of spontaneous facial expressions. Mental status examination was normal. Eye movements were absent in all directions. The pupils responded to light. The visual fields were full to confrontation but her visual acuity was reduced even with correction. The fundi showed pigmentary degeneration. Cataracts were not present. Hearing was normal. Motor examination revealed weakness of neck muscles and proximal muscle groups in the lower extremities. DTRs were reduced. Plantar reflexes were flexor. No myotonia was present and there was no fatigability. Cerebellar testing revealed intact finger to nose, slow rapid alternating movements in the upper extremities with mild ataxia, moderate heel to shin ataxia and gait ataxia. Romberg’s testing was steady eyes open and closed. Sensory examination showed preserved sensation to primary modalities. An EKG showed incomplete heart block.
Summarize the Case in 1-2 sentences. 18 year-old female presents with progressive external opthalmoplegia of 12 years, progressive proximal muscle weakness for the last six months, pigmentary degeneration of the retina, and an incomplete heart block apparent on examination. In addition, ataxia, short stature, and ptosis were noted, although fatiguability, mental status changes, and family history were all absent. good, a bit on the long side Discuss lesion localization on the basis of the physical examination. The lesion is localized to muscle. In addition, myopathy hallmarks such as proximal muscle weakness, bilateral presentation, facial involvement, and insidious onset are all present, without fatiguability. insidious onset does not appear relevant to answering this question Discuss underlying pathogenesis on the basis of clinical course. This is a chronic, slowly progressive course suggesting a myopathy. Due to the slow onset, a metabolic or mitochondrial myopathy is likely. Muscular dystrophy is also consistent with this onset and course, though not with the clinical presentation. progressive course does not suggest a myopathy (myopathies may be sudden, subacute, chronic) like any other neurological problem. rather a chronic progressive course suggests a degenerative or metabolic process. Do not give diagnoses eg. mitochondrial disorder or dystrophy as an answer to this question. It does not follow from the time intensity profile alone ! Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses. Kearns-Sayre Syndrome. Other diagnoses: Metabolic myopathy Muscular dystrophy give examples of each other mitochondrial disorders resulting from single point mutations rather than deletions are also in the differential Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis. 1. Muscle biopsy with special stains (i.e. Mallory's) would reveal ragged, red fibers consistent with Kearns-Sayre. 2. Gene sequencing would reveal a single deletion in mitochondrial DNA consistent with Kearns-Sayre. good Indicate complications of the disease and ancillary tests that would help evaluate them. Cardiac arrest (most common cause of death): monitor with periodic ECG. Diabetes mellitus: monitor with periodic blood glucose. Hyperparathyroidism: monitor with PTH level. Sensorineural hearing loss: Weber and Rinne tests. good Discuss how the underlying pathophysiology is relevant in the management of this patient. The Kearns-Sayre syndrome is caused by a deletion in the mitochondrial DNA which usualy occurs in the zygote. This results in a loss of genes needed for oxidative phosphorylation. The impairment of ATP production that results affects tissues with high demand for energy: neural tissue, cardiac muscle and skeletal muscle. Hence, Kearns-Sayre produces the classic triad of progressive external opthalmoplegia, pigmentary degeneration of the retina, and heart block. A mixture of mutant and wild-type mitochondrial DNA is seen within the same cell (heteroplasmy). Different concentrations of mutant DNA-containing mitochondria are present in different cells. Since muscle cells have such a high concentration of mitochondria, symptoms first present in muscle (e.g. cardiac, extraocular, and proximal lower extremity muscles). Since all mitochondria are maternally inherited (from the oocyte), females can pass Kearns-Sayre on to their offspring. Therefore, genetic counseling is advised for Kearns-Sayre patients. Prognosis for Kearns-Sayre patients is poor, as most die of cardiac arrest in their third or fourth decade. Therefore, genetic counseling and periodic ECG monitoring are essential. Pacemaker implantation is a possibility. very good

Case 12 2/23/99 Myopathy

Case discussion

This 18-year old female was evaluated for ophthalmoplegia and progressive muscle weakness. At the age of 6 years she was noted to have a squint and was given glasses. At seven she complained of double vision that gradually resolved. She did reasonably well until her early teens when she found herself unable to compete with other children at play. Approximately one year prior double vision recurred. For the past 6 months she complained of progressive generalized weakness and has difficulty rising from a seated to standing position.

On examination she was of short stature with ptosis and a paucity of spontaneous facial expressions. Mental status examination was normal. Eye movements were absent in all directions. The pupils responded to light. The visual fields were full to confrontation but her visual acuity was reduced even with correction. The fundi showed pigmentary degeneration. Cataracts were not present. Hearing was normal. Motor examination revealed weakness of neck muscles and proximal muscle groups in the lower extremities. DTRs were reduced. Plantar reflexes were flexor. No myotonia was present and there was no fatigability. Cerebellar testing revealed intact finger to nose, slow rapid alternating movements in the upper extremities with mild ataxia, moderate heel to shin ataxia and gait ataxia. Romberg’s testing was steady eyes open and closed. Sensory examination showed preserved sensation to primary modalities. An EKG showed incomplete heart block.

Summarize the Case in 1-2 sentences.

18 year-old female presents with progressive external opthalmoplegia of 12 years, progressive proximal muscle weakness for the last six months, pigmentary degeneration of the retina, and an incomplete heart block apparent on examination. In addition, ataxia, short stature, and ptosis were noted, although fatiguability, mental status changes, and family history were all absent.

good, a bit on the long side

Discuss lesion localization on the basis of the physical examination.

The lesion is localized to muscle. In addition, myopathy hallmarks such as proximal muscle weakness, bilateral presentation, facial involvement, and insidious onset are all present, without fatiguability.

insidious onset does not appear relevant to answering this question

Discuss underlying pathogenesis on the basis of clinical course.

This is a chronic, slowly progressive course suggesting a myopathy. Due to the slow onset, a metabolic or mitochondrial myopathy is likely. Muscular dystrophy is also consistent with this onset and course, though not with the clinical presentation.

progressive course does not suggest a myopathy (myopathies may be sudden, subacute, chronic) like any other neurological problem. rather a chronic progressive course suggests a degenerative or metabolic process. Do not give diagnoses eg. mitochondrial disorder or dystrophy as an answer to this question. It does not follow from the time intensity profile alone !

Indicate one likely clinical diagnosis. List (or classify) alternative diagnoses.

Kearns-Sayre Syndrome.

Other diagnoses:
Metabolic myopathy
Muscular dystrophy

give examples of each other mitochondrial disorders resulting from single point mutations rather than deletions are also in the differential

Indicate 2 ancillary tests that would assist in confirming or refuting the clinical diagnosis. Indicate the test results that would confirm the clinical diagnosis.

1. Muscle biopsy with special stains (i.e. Mallory's) would reveal ragged, red fibers consistent with Kearns-Sayre.

2. Gene sequencing would reveal a single deletion in mitochondrial DNA consistent with Kearns-Sayre.

good

Indicate complications of the disease and ancillary tests that would help evaluate them.

Cardiac arrest (most common cause of death): monitor with periodic ECG. Diabetes mellitus: monitor with periodic blood glucose. Hyperparathyroidism: monitor with PTH level. Sensorineural hearing loss: Weber and Rinne tests.

good

Discuss how the underlying pathophysiology is relevant in the management of this patient.

The Kearns-Sayre syndrome is caused by a deletion in the mitochondrial DNA which usualy occurs in the zygote. This results in a loss of genes needed for oxidative phosphorylation. The impairment of ATP production that results affects tissues with high demand for energy: neural tissue, cardiac muscle and skeletal muscle.

Hence, Kearns-Sayre produces the classic triad of progressive external opthalmoplegia, pigmentary degeneration of the retina, and heart block. A mixture of mutant and wild-type mitochondrial DNA is seen within the same cell (heteroplasmy). Different concentrations of mutant DNA-containing mitochondria are present in different cells. Since muscle cells have such a high concentration of mitochondria, symptoms first present in muscle (e.g. cardiac, extraocular, and proximal lower extremity muscles). Since all mitochondria are maternally inherited (from the oocyte), females can pass Kearns-Sayre on to their offspring. Therefore, genetic counseling is advised for Kearns-Sayre patients. Prognosis for Kearns-Sayre patients is poor, as most die of cardiac arrest in their third or fourth decade. Therefore, genetic counseling and periodic ECG monitoring are essential. Pacemaker implantation is a possibility.

very good