Clinical Reasoning: A 62-year-old woman with deafness, unilateral visual loss, and episodes of numbness
Brian C. Callaghan, MD,
Sashank Prasad, MD and
Steven L. Galetta, MD
From the Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia.
Address correspondence and reprint requests to Dr. Brian C. Callaghan, Department of Neurology, University of Michigan, 1914 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48104-0316 bcallagh{at}med.umich.edu
In May 2007, a 62-year-old woman presented with two episodesof right-hand numbness. The episodes were accompanied by profoundfatigue. Each event lasted 5 minutes, and both occurred withina 2-week period. She also recalled an episode of right-sidednumbness 30 years previously. She had a past medical historyof hypothyroidism, hypertension, hypercholesterolemia, and multiplemiscarriages. About 15 years ago, she began losing hearing inher left and then right ear, and she had been completely deaffor the last 8 years. Prior testing had revealed that the patienthad sensorineural hearing loss, but the etiology could not bedetermined. Family and social history were unremarkable.
Questions for consideration:
What is the differential diagnosis for episodic neurologic abnormalities?
The differential diagnosis of transient sensory dysfunctionis broad and includes TIA, complicated migraine, seizure, metabolicderangement, peripheral nerve compression, compressive myelopathy,multiple sclerosis (MS), and conversion disorder.1 Particularlyin patients over the age 55, transient neurologic attacks thatare focal, nonfocal, or a mixture of both are associated withan increased risk of stroke. Therefore, an evaluation of ourpatient should include carotid ultrasound, transthoracic echocardiogram,and head CT or MRI of the brain.2 The history of multiple miscarriagesraises the suspicion for antiphospholipid syndrome, which maycause a hypercoagulable state. Anticardiolipin antibodies, antibeta-2 glycoprotein antibodies, and lupus anticoagulant assayscould be performed to investigate this possibility. An EEG maybe considered to identify epileptiform discharges, especiallygiven the patient’s post-event fatigue.
A diagnostic evaluation for the cause of her two episodes ofnumbness was unrevealing. Then, in January 2008, the patientnoted blurred vision in her left eye that progressed over 3days. She denied pain on eye movements, photopsia, metamorphopsia,or other neurologic deficit. Initial eye examination showeda left relative afferent defect and a normal-appearing leftoptic nerve head. An MRI of the brain was performed and revealedT2 and fluid-attenuated inversion recovery (FLAIR) signal abnormalityin the subcortical and deep white matter, without enhancementwith gadolinium. A diagnosis of optic neuritis was made andthe patient received high-dose IV steroids for 5 days. However,her visual function did not improve over the next 2 months.At this time she came under our care.
Question for consideration:
What is the differential diagnosis for the constellation ofepisodic numbness, new visual loss, and progressive hearingloss?
Our patient has had episodes of transient neurologic dysfunction,visual loss, and a past history of sensorineural deafness. Fewconditions can completely account for this symptom complex.Wolfram syndrome is a rare, heterogeneous, inherited neurodegenerativedisorder characterized by diabetes insipidus, diabetes mellitus,optic atrophy, and sensorineural deafness. While this syndromewould tie together visual and sensorineural hearing loss, itwould not account for her transient numbness. Furthermore, shehad no evidence of diabetes, and there was no family historyof a similar disorder. Late onset MS was also considered butthe clinical course of the visual loss was atypical for opticneuritis given the absence of pain and the lack of subsequentvisual improvement. Bilateral hearing loss is also rare in MS.Another possibility was vitamin B1 deficiency. This conditioncan cause optic neuropathy and sensorineural hearing loss, butusually in combination with confusion, ataxia, and nystagmus,which our patient did not demonstrate. We also considered Susacsyndrome, which consists of the triad of encephalopathy, branchretinal artery occlusions, and hearing loss. This conditionis due to a microangiopathy affecting the precapillary arteriolesof the brain, retina, and inner ear. However, an interval of30 years between the onset of her progressive hearing loss andher current symptoms would be uncharacteristic of this disorder.
Several mitochondrial disorders can account for her major symptomsand would be highest on the differential at this point. Mitochondrialdisorders in general have clinical heterogeneity, in part dueto heteroplasmy (differential amounts of mutated DNA and normalDNA within each tissue). Also, each tissue has a different thresholdat which the proportion of mutant mitochondrial (mt) DNA causessymptoms.3 Mitochondrial encephalopathy with lactic acidosisand stroke-like episodes (MELAS), myoclonic epilepsy with ragged-redfibers (MERRF), and chronic progressive external ophthalmoplegiaoften include sensorineural hearing loss; on the other hand,Leber hereditary optic neuropathy, neuropathy, ataxia, and retinitispigmentosa, and maternally inherited Leigh syndrome often involvevision, but not hearing (table).3 Given the history of suddenonset numbness, MELAS stands out as a possible culprit. Thisdisorder can present with a wide range of clinical symptomsincluding seizures, ataxia, stroke-like episodes, neuropathy,myopathy, sensorineural hearing loss, and encephalopathy.3 Althoughour patient is older than the typical age at presentation, withgreater than 90% of patients presenting with a severe coursebefore the age of 40, there are many reports of patients withMELAS and other mitochondrial disorders presenting later inlife.4 Although our patient did not have a family history suggestingmaternal inheritance, spontaneous mutations occur in a subsetof patients with MELAS.
Table Clinical features of mitochondrial diseases3,10
Physical examination revealed that the patient was cachecticand had short stature. She weighed 65 pounds. Her blood pressureand heart rate were normal. Mental status testing revealed normalorientation, attention, concentration, memory, and language.Acuity was 20/20-2 in the right eye with 8/11 color plates,and she could count fingers at 4 feet in the left eye with 0/11color plates. With pinhole, she was occasionally able to seethe 20/200 line with the left eye. Confrontation and computerizedvisual fields were normal in the right eye, and revealed a centralscotoma and inferior altitudinal defect in the left eye (figure 1).The pupillary light response was brisk on the right and sluggishin the left eye, and there was a left relative afferent pupildefect. Her ocular motility examination revealed mildly restrictedupgaze for saccades, pursuit, and oculocephalic movements. Ductionswere otherwise full. Funduscopic examination revealed myopicchanges bilaterally and optic atrophy in the left eye. Therewas subtle right optic nerve atrophy. She was deaf bilaterally.She had dysarthric speech, but facial strength and sensationwere normal. She had 4/5 strength proximally and 5/5 strengthdistally. On sensory examination, she had evidence of a length-dependentneuropathy with decreased vibration and temperature sensationup to her elbows and mid-thighs. There was no dysmetria. Shehad slight difficulty with tandem walk. There was no Rombergsign. Her deep tendon reflexes were absent.
Three features of this examination are particularly important.First, short stature is seen in many mitochondrial disordersand suggests a longstanding disorder affecting growth and development.Second, the patient has proximal weakness, fitting a myopathicpattern. Mitochondrial disorders commonly involve multiple organsystems, and are particularly likely to cause myopathy. Finally,she has absent reflexes and length-dependent sensory loss indicativeof neuropathy. Among disorders that cause concomitant neuropathyand myopathy, mitochondrial disease is on a fairly short listwhich also includes rheumatologic conditions such as Sjögrensyndrome, sarcoidosis, toxicity from agents such as colchicine,amyloidosis, thyroid disease, or critical illness.
The patient’s brain MRI was reviewed at our institutionand revealed prominent, symmetric T2 and FLAIR signal abnormalityin the subcortical and deep white matter and stippling of thebasal ganglia. There was no enhancement with gadolinium (figure 2).
Figure 2 MRI of the brain: Fluid-attenuated inversion recovery (FLAIR) sequences
MRI of the brain showed prominent symmetric T2 and FLAIR signal abnormality in the subcortical and deep white matter and stippling of the basal ganglia. There was no enhancement with gadolinium. The pons had significant T2 and FLAIR abnormality as well.
Electromyography revealed excessive low amplitude, short duration,polyphasic motor units with a decreased recruitment ratio andearly interference pattern consistent with a mild myopathy.There was also evidence of a mild axonal polyneuropathy on nerveconduction studies.
Optical coherence tomography (OCT) (figure 3) showed a retinalnerve fiber layer thickness of 80.03 µm in the right eyeand 54.79 µm in the left eye (normal, 104 µm ±12). An electroretinogram (ERG) had normal results.
Figure 3 Ocular coherence tomography showing a retinal nerve fiber layer (RNFL) thickness of 80.03 µm in the right eye and 54.79 µm in the left eye (normal, 104 µm ± 12)
The retinal nerve fiber layer in the left eye is thinnest in the superior, inferior, and temporal regions. TEMP = temporal; SUP = superior; NAS = nasal; INF = inferior.
Questions for consideration:
How does the MRI of the brain change the differential diagnosis?
Why is the electromyography important?
What does the combinationof the OCT and ERG tell us about thelocalization of the patient’svisual loss?
The brain MRI revealed diffuse and symmetric abnormality inthe white matter with pathologic changes in the basal ganglia.This patient was treated for optic neuritis earlier in her clinicalcourse but it should be noted that the white matter abnormalitieson the MRI were atypical for MS. Symmetric, nonenhancing lesionsof the subcortical and deep white matter without enhancementof the optic nerves would be unusual for a patient with MS andacute optic neuritis. This fact underscores the importance notonly of brain imaging in the diagnosis of MS but also the properinterpretation of the scan results. Furthermore, the patientwas treated with 5 days of IV steroids, whereas the currentstandard of care based on the Optic Neuritis Treatment Trialis 3 days of IV steroids followed by an oral prednisone taper.On the other hand, the combination of the MRI abnormalitiesmight suggest the diagnosis of cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy (CADASIL),which results from a NOTCH 3 gene mutation. Patients with CADASILtypically present with multiple subcortical infarcts, migraines,dementia, and psychiatric symptoms. The MRI abnormality in thiscondition reveals T2/FLAIR abnormalities in the subcorticaland deep white matter including the anterior temporal lobe andexternal capsule.5 Although our patient’s MRI suggestedthis condition, other clinical features such as optic nerveand cochlear nerve dysfunction did not.
In MELAS, there can be a wide variety of MRI abnormalities.Classically, the prominent abnormality is in the cortical graymatter, extending across vascular territories, without restricteddiffusion. In addition, there is high T1 signal in the basalganglia.6 However, there have been several reports where theMRI abnormality was limited to the white matter.6
Our patient’s electromyography and nerve conduction studiesconfirmed the coexistence of myopathy and neuropathy, in keepingwith a mitochondrial disorder with multiorgan involvement. Onestudy found that almost all patients with MELAS had clinicalfindings suggestive of neuropathy, with confirmation on nerveconduction studies in 77%.7
The OCT and ERG results confirmed that our patient has dysfunctionof the left optic nerve with normal retinal function. OCT measuresthe thickness of the retinal nerve fiber layer to quantify theextent of axonal loss.8 ERG measures the electrical responsesof photoreceptors in the retina and therefore provides an indicationof retinal integrity and function.
There are a few ancillary tests that can be helpful in the diagnosisof MELAS. Magnetic resonance spectroscopy of the brain can identifylactate peaks when considering mitochondrial disorders. Serumlactic acid levels are often abnormal in MELAS. Our patienthad a lactate level of 16 mg/dL (normal range, 4–16) anda pyruvate level of 0.14 mg/dL (range, 0.3–0.7). Her lactatewas at the high end of normal and her lactate/pyruvate ratiowas elevated. These values are consistent with the metabolicdisturbance found when mitochondrial oxidative phosphorylationis not functioning properly. For definitive diagnosis, a testwas sent for the common MELAS mutations and she was found tohave the A3243G mt DNA mutation.
Although there is no established treatment for MELAS, rationaltherapeutic approaches based upon the associated biochemicalabnormalities include supplementation with levocarnitine, coenzymeQ10, and vitamin B complex.4 MELAS causes dysfunction of complexI of the respiratory chain and, therefore, decreased beta oxidationof long-chain fatty acids. Levocarnitine aids in the transportof long-chain fatty acids into the mitochondrion, and supplementationmay help increase fatty acid oxidation. Coenzyme Q10 transferselectrons from complexes I and II to complex III and also stabilizesthese complexes within the mitochondrion membrane. These functionsmay provide a beneficial antioxidant effect. Vitamin B complexcontains thiamine, riboflavin, and nicotinamide, which all haveproposed biochemical mechanisms to aid in repairing oxidativephosphorylation.4 Additionally, there are new data suggestingthat arginine therapy may also benefit these patients, possiblyby increasing nitric oxide levels and thereby reversing theimpairment of vasodilation in this disorder. In a controlledclinical trial, arginine therapy reduced the severity, frequency,and disability resulting from stroke-like episodes in MELAS.9Side effects of arginine therapy, however, may include severehypotension. Therefore, more data are clearly needed to proposethis treatment in all patients.
Patients with MELAS must also receive appropriate genetic counseling.Typically, there is a maternal inheritance pattern, in whichall children of an affected mother are also affected. Giventhe clinical heterogeneity in mitochondrial disorders, theseaffected children can have a wide spectrum of phenotypes. Inaddition, there are rare autosomal mutations that can also causethe MELAS phenotype. Our patient had the most common mitochondrialmutation. As a result, all of her children would be expectedto be carriers and she should be counseled appropriately. Sinceher parents were not affected, she most likely had a de novomutation in her mitochondrial DNA.
Our patient had bilateral sensorineural deafness, acute opticneuropathy, and transient episodes of numbness. These clinicalfeatures coupled with her ancillary testing including the MRIof the brain, electromyography, and ocular testing allowed forthe final diagnosis of MELAS. Genetic testing confirmed thishypothesis.
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