Neurology Publish Ahead of PrintDOI: 10.1212/WNL.0000000000010464

Clinical Reasoning: A 57-year-old female presented with progressive ataxia and falls

Author: Adnan Badahdah, MD, FRCPC

Adnan Badahdah, Dalhousie University, Department of Medicine, Halifax, NS, Canada. University of

Jeddah, Department of Medicine, Jeddah, Saudi Arabia

Search Terms: All Clinical Neurology, EMG, Prion disease, Peripheral neuropathy, Chronic inflammatory

demyelinating polyneuropathy

Publication history: This manuscript was not published before.

Submission Type: Clinical Reasoning

Title Character count: 54

Number of Tables: 1

Number of Figures: 1

Word Count of Abstract: 0

Word count of Paper: 1428

Corresponding Author: Adnan Badahdah (Adnan.badahdah@gmail.com)

Neurology® Published Ahead of Print articles have been peer reviewed and accepted for

publication. This manuscript will be published in its final form after copyediting, page

composition, and review of proofs. Errors that could affect the content may be corrected during

these processes.

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Published Ahead of Print on August 4, 2020 as 10.1212/WNL.0000000000010464

Study Fund:

No targeted funding reported

Disclosure:

The author reports no disclosures relevant to the manuscript.

Section 1

A 57-year-old female presented with progressive ataxia and falls. She was in her usual state of health

until she developed sudden onset of progressive imbalance for a month. She then presented to an

emergency department. Examination revealed significant vibration sensation impairment and

proprioceptive loss, with normal pinprick and temperature sensation; sensory ataxia with

pseudoathetosis in the hands; no finger to nose incoordination; normal rapid alternating movements of

upper extremities; heel to shin incoordination; diminished deep tendon reflexes; wide-based gait and

positive Romberg test. She did not have cognitive impairment, nystagmus, dysarthria, weakness, muscle

atrophy or fasciculations.

Questions for consideration:

1. What is the localization for her presentation? How can you differentiate between cerebellar and

sensory ataxia?

2. What are the differential diagnoses at this stage?

GO TO SECTION 2

Section 2

The patient presented with subacute progressive sensory ataxia with no significant weakness. The

marked proprioceptive loss is an explanation for the ataxia. Absence of nystagmus, dysarthria and upper

extremities incoordination made a cerebellar lesion less likely. Diminished deep tendon reflexes suggest

a peripheral nervous system lesion. These findings are suggestive of subacute sensory large fiber

involvement with no apparent motor fiber involvement. The sensory disorder could result from lesions

of posterior column in the spinal cord, the dorsal root ganglions or large sensory fibers in the peripheral

nerves. This could happen due to various disorders: metabolic disorders like vitamin B12 or E deficiency;

Sjogren syndrome (autoimmune disorder usually with dry eyes and dry mouth); infections like HIV,

syphillis and HSV; paraneoplastic disorders; pure sensory inflammatory demyelinating

polyradiculopathy; paraproteinemias like MGUS; and toxicity from cisplatin and analogs or excess

vitamin B6 (unlikely as the patient was not taking those medications).

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Question for consideration:

1. What investigations can narrow the differential diagnoses?

GO TO SECTION 3

Section 3

Extensive investigations showed no evidence of an immunological, infectious or metabolic disorder.

Cerebral spinal fluid (CSF) showed 5 WBCs, normal glucose, slightly elevated protein 0.67 g/L (normal <

0.45 g/L); cytology showed no malignant cells.

Nerve conduction studies (Table) revealed findings in keeping with a possible demyelinating

polyneuropathy or polyradiculoneuropathy involving motor and sensory fibers according to European

Federation of Neurological Societies criteria as right peroneal motor study recording at extensor

digitorum bervis showed distal latency prolongation more than 50% above upper limit of normal values

and a reduction in conduction velocity more than 30% below the lower limit of normal values. There was

focal slowing in the right ulnar nerve at the level of the elbow, possibly due to compression. Needle

electromyography showed low-grade fibrillation potentials in right first dorsal interosseous and

irritability in gastrocnemius. There was evidence of mild to moderate old axon loss, with reinnervation in

upper and lower limb muscles.

An acquired polyneuropathy with diffuse, patchy demyelination and minor axonal involvement was

diagnosed. CT of the chest, abdomen and pelvis showed no evidence of malignancy, and paraneoplastic

antibody panel was negative.

Question for consideration:

1. What treatment options would you consider?

2. What are your expectations?

GO TO SECTION 4

Section 4

The pervious investigations showed mild inflammation in the CSF and patchy demyelinating lesions in

the electrodiagnostic study. These findings could be consistent with inflammatory demyelinating

polyneuropathy. A course of IVIg 400 mg/kg daily for 5 days was given (ideally you want to see

improvement in patient condition or at least no worsing). Plasma exchange is another option which was

not used in this case.

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Unfortunately, IVIG course produced no improvement and she continued to decline. Two months later,

she started to have cognitive impairment; short-term memory became severely impaired with time.

Worsening ataxia in the limbs was noted. She became bedridden. MRI brain (fig: A,B) showed T2/FLAIR

hyperintensity in the caudate and putamen, with reverse hot cross bun sign in the pons, which may be

seen with toxic/metabolic disturbances or CJD.

Question for consideration:

1. How would you confirm your diagnosis?

GO TO SECTION 5

Section 5

Electroencephalogram was normal, despite the patient's cognitive decline. A second CSF study showed

endpoint quaking-induced conversion (EP-QuIC) was positive for disease-associated isoforms of the

prion protein (PrPd). Elisa protein assay for 14-3-3 gamma was 71,791 AU/mL (threshold >20,000

AU/mL), and microtubule-associated protein tau (hTAU) was 6589 pg/mL (threshold >976 pg/mL). This

was considered positive for sporadic CJD.

She continued to deteriorate and died five months after symptom onset.

The brain at autopsy weighed 1172 grams. Grossly, the lateral ventricles showed mild symmetric

enlargement. There was focal congestion in the right superomedial frontal white matter. The cerebellar

hemispheres were atrophic. Microscopic examination revealed widespread spongiosis (fig: C,D). In

cortical sections, the cingulate gyrus showed significant disease, with moderate changes in the frontal

cortex and milder changes involving the temporal, parietal and occipital cortices. There was marked

involvement of the anterior and posterior hippocampus and caudate nucleus, with mild-moderate

changes in the amygdala and thalamus. The midbrain, pons and medulla showed patchy spongiosis. The

cerebellum showed extensive involvement with associated severe foliar atrophy. Unfortunately, no

peripheral nerve tissue was available for examination.

Discussion

Human prion diseases, including Creutzfeldt–Jakob disease (CJD), are transmissible diseases that

predominantly involve the central nervous system (CNS). Some patients with CJD show subclinical signs

of peripheral nerve involvement, such as areflexia, ataxia, length-dependent sensory disturbance, and

amyotrophy, later in the disease. [1-5] Electrophysiological and histological studies have been reported

to show the presence of demyelinating or axonal neuropathy, or loss of anterior horn cells in the spinal

cord. [1-6]

Demyelinating polyneuropathy is a rare consequence of CJD; only a few patients have been described in

the literature. [3-5] Early involvement of the PNS is more unexpected in sporadic CJD than in infectious

forms of the disease that involve a peripheral route of contamination. Neuropathological information on

the PNS are rare in CJD. An extensive accumulation of PrPsc in the dorsal root ganglia and autonomic

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

ganglia have been reported [7]. However, Antoine et al. performed a pathological analysis of the PNS in

a sporadic CJD patient presenting with demyelinating polyneuropathy which did not show PrPsc

accumulation [3].

This is a case of sporadic CJD in whom a rapidly progressive demyelinating sensorimotor neuropathy was

the initial presentation. Initially you need to consider various disorders: metabolic disorders like vitamin

B12 or E deficiency; Sjogren syndrome (autoimmune disorder usually with dry eyes and dry mouth);

infections like HIV, syphillis and HSV; paraneoplastic disorders; pure sensory inflammatory

demyelinating polyradiculopathy; paraproteinemias like MGUS; and toxicity from cisplatin and analogs

or excess vitamin B6. As soon as patient developed central nervous system symptoms, your approach

will change to include disorders that could affect central and peripheral nervous system. Though CJD is a

rare cause of central and peripheral nervous system involvement, it should be in the differential

diagnosis as this case demonstrated.

Previously published reports of peripheral nervous system (PNS) involvement in CJD, described patients

with advanced CJD; rarely had polyneuropathy as the initial manifestation. Neufeld et al [1] reported

two familial cases with a codon 200 mutation of the PrP gene. The first patient had an 18-month history

of CJD and was found to have axonal polyneuropathy without demyelination; the second patient had

triphasic wave on EEG and later was found to have evidence of severe demyelination on

electrodiagnostic testing. Niewiadomska et al [2] studied nerve conduction and EMG changes in 16

patients with definite CJD: 3 patients had amyotrophy or absent deep tendon reflexes and

electrophysiological features of PNS involvement were demonstrated in 14 patients (motor neuropathy,

axonal or demyelinating neuropathy). Antoine et al [3] reported a case of familial CJD with early

dementia, cerebellar signs and polyneuropathy. Esiri et al [4] describe a patient with a 3-month history

of CJD, with early cerebellar signs and painful neuropathy. Sadeh et al [5] reported a case with a 20-

month history of CJD, who developed late signs of polyneuropathy. Kovacs et al [8] reported a case of

demyelinating peripheral neuropathy and amyotrophy, presenting simultaneously with symptoms of

CJD. Dorien et al [9] reported a genetic CJD case presenting with a CIDP-like picture. Baiardi et al [10]

demonstrated in 303 sCJD patients, that about 40% of them had symptoms and signs suggestive of PNS

involvement and occur at disease onset in 9.3%. While extensive investigations suggested a pattern

characterized by prominent signs of axonal damage with secondary demyelination. To this day, there is

no consensus as to how CJD causes polyneuropathy, but this finding has been associated with some

subtypes of the disease.

In conclusion, this case suggests that sporadic CJD is a neurologically widespread disease of the nervous

system that may be revealed by the early appearance of demyelinating peripheral neuropathy. CJD

should be in the differential diagnosis of patients who present with a CIDP picture, especially if there is

rapid disease progression and no response to immunotherapy and if there are additional symptoms

suggesting CNS involvement.

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Appendix 1: Author

Name Location Contribution

Adnan Badahdah MD,

FRCPC

Dalhousie University,

Halifax

University of Jeddah,

Jeddah

Data collection,

drafting and revision of

manuscript

References:

1. Neufeld MY, Josiphov J, Korczyn AD. Demyelinating peripheral neuropathy in Creutzfeldt-Jakob

disease. Muscle Nerve 1992;15:1234–9.

2. Niewiadomska M, Kulczycki J, Wochnik-Dyjas D, et al. Impairment of the peripheral nervous

system in Creutzfeldt-Jakob disease. Arch Neurol 2002;59:1430–6.

3. Antoine JC, Laplanche JL, Mosnier JF, et al. Demyelinating peripheral neuropathy with

Creutzfeldt-Jakob disease and mutation at codon 200 of the prion protein gene. Neurology

1996;46:1123–7.

4. Esiri MM, Gordon WI, Collinge J, et al. Peripheral neuropathy in Creutzfeldt-Jakob disease.

Neurology 1997;47:784.

5. Sadeh M, Chagnac Y, Goldhammer Y. Creutzfeldt-Jakob disease associated with peripheral

neuropathy. Isr J Med Sci 1990;26:220–2.

6. Chapman J, Brown P, Goldfarb LG, et al. Clinical heterogeneity and unusual presentations of

Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation. J Neurol

Neurosurg Psychiatry 1993;56:1109–12.

7. Lee CC, Kuo LT, Wang CH, Scaravilli F, An SF (2005) Accumulation of prion protein in the

peripheral nervous system in human prion disease. J Neuropathol Exp Neurol 64:716–721

8. Kovacs T, Aranyi Z, Szirmai I, Lantos PL. Creutzfeldt-Jakob disease with amyotrophy and

demyelinating polyneuropathy. Arch Neurol 2002;59:1811–1814.

9. Dorien W, Maarten S, Philippe D, Christine V, Thomas T, Gabor K, Philip V. Genetic Creutzfeldt-

Jacob disease mimicking chronic inflammatory demyelinating polyneuropathy. Neurol

Neuroimmunol Neuroinflamm 2015;2:e173.

10. Baiardi S, Redaelli V, Ripellino P, Rossi M, Franceschini A, Moggio M, Sola P, Ladogana A, Fociani

P, Magherini A, Capellari S, Giese A, Caughey B, Caroppo P, Parchi P. Prion-related peripheral

neuropathy in sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. 2018 Oct 24.

pii: jnnp-2018-319221. doi: 10.1136/jnnp-2018-319221.

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Table: Nerve conduction studies

Nerve and Site Latency Amplitude Segment Distance Conduction

Velocity

Motor Nerve Conduction

Peroneal.R

Ankle 10.4 ms 0.2 mV EDB-Ankle 85 mm m/s

Fibula (head) 21.7 ms 0.2 mV Ankle-Fibula

(head)

305 mm 27 m/s

Popliteal fossa 23.6 ms 0.2 mV Ankle-

Popliteal fossa

392 mm 30 m/s

Peroneal.R

Fibula (head) 3.1 ms 7.7 mV Tibialis

anterior-Fibula

(head)

105 mm m/s

Popliteal fossa 6.0 ms 8.0 mV Fibula (head)-

Popliteal fossa

102 mm 35 m/s

Tibial.R

Ankle 6.1 ms 6.8 mV Abductor

hallucis-Ankle

85 mm m/s

Popliteal Fossa 13.9 ms 3.9 mV Ankle-

Popliteal Fossa

355 mm 46 m/s

Ulnar.R

Wrist 5.0 ms 10.2 mV ADM-Wrist 65 mm m/s

Below elbow 8.4 ms 8.7 mV Wrist-Below

elbow

202 mm 59 m/s

Above elbow 12.3 ms 7.0 mV Wrist-Above

elbow

318 mm 44 m/s

Median.R

Wrist 12.6 ms 4.0 mV APB-Wrist 70 mm m/s

Elbow 18.1 ms 3.8 mV Wrist-Elbow 216 mm 39 m/s

F-Waves

Tibial.R 63.0 ms 1083 mm

Ulnar.R 38.3 ms 642 mm

Sensory Nerve Conduction

Sural.R

Mid Calf NR ms NR µV Ankle-Mid Calf 140 mm m/s

Superficial peroneal.R

Ankle NR ms NR µV Lower Leg-

Ankle

140 mm m/s

Ulnar.R

Wrist 4.9 ms 4.9 µV Fifth-Wrist 110 mm m/s

Elbow 12.6 ms 1.4 µV Wrist-Elbow 345 mm 46 m/s

EDB, extensor digitorum brevis; ADM, abductor digiti minimi; APB, abductor pollicis brevis

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

Figure: MRI brain and brain histopathology

(A) T2 FLAIR image of the brain showing hyperintensities in the medial thalamus and basal ganglia. (B) T2

FLAIR image of the brain showing reverse hot cross bun in pons. (C) Cingulate gyrus. Spongiform

appearance with empty vacuoles between neurons, and no inflammatory cells. (D) Cerebellum. Similar

changes in the cerebellar cortex, especially in the molecular layer shown here.

ACCEPTED

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited

DOI 10.1212/WNL.0000000000010464 published online August 4, 2020Neurology 

Adnan BadahdahClinical Reasoning: A 57-year-old female presented with progressive ataxia and falls

This information is current as of August 4, 2020

ServicesUpdated Information &

464.citation.fullhttp://n.neurology.org/content/early/2020/08/04/WNL.0000000000010including high resolution figures, can be found at:

Subspecialty Collections

http://n.neurology.org/cgi/collection/prion_diseasePrion disease; see Infections/prion

http://n.neurology.org/cgi/collection/peripheral_neuropathyPeripheral neuropathy

http://n.neurology.org/cgi/collection/emgEMG

ing_polyneuropathyhttp://n.neurology.org/cgi/collection/chronic_inflammatory_demyelinatChronic inflammatory demyelinating polyneuropathy

http://n.neurology.org/cgi/collection/all_clinical_neurologyAll Clinical Neurologyfollowing collection(s): This article, along with others on similar topics, appears in the

  Permissions & Licensing

http://www.neurology.org/about/about_the_journal#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in

  Reprints

http://n.neurology.org/subscribers/advertiseInformation about ordering reprints can be found online:

rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright © 2020 American Academy of Neurology. All

® is the official journal of the American Academy of Neurology. Published continuously sinceNeurology